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SYNTHESIS OF CRAC CHANNEL INHIBITORS
CROSS-REFERENCE
[0001] This application claims the benefit of U.S. Provisional Application No.
62/843,822, filed
May 6, 2019, which is hereby incorporated by reference in its entirety herein.
BACKGROUND
[0002] Calcium plays a vital role in cell function and survival. For example,
calcium is a key
element in the transduction of signals into and within cells. Cellular
responses to growth factors,
neurotransmitters, hormones and a variety of other signal molecules are
initiated through
calcium-dependent processes.
[0003] Virtually all cell types depend in some manner upon the generation of
cytoplasmic Ca'
signals to regulate cell function, or to trigger specific responses. Cytosolic
Ca2+ signals control a
wide array of cellular functions ranging from short-term responses such as
contraction and
secretion to longer-term regulation of cell growth and proliferation. Usually,
these signals
involve some combination of release of Ca' from intracellular stores, such as
the endoplasmic
reticulum (ER), and influx of Ca' across the plasma membrane. In one example,
cell activation
begins with an agonist binding to a surface membrane receptor, which is
coupled to
phospholipase C (PLC) through a G-protein mechanism. PLC activation leads to
the production
of inositol 1,4,5-triphosphate (IP3), which in turn activates the IP3 receptor
causing release of
Ca2+ from the ER. The fall in ER Ca2+ then signals to activate plasma membrane
store-operated
calcium (SOC) channels.
[0004] Store-operated calcium (SOC) influx is a process in cellular physiology
that controls such
diverse functions such as, but not limited to, refilling of intracellular Ca"
stores (Putney et al.
Cell, 75, 199-201, 1993), activation of enzymatic activity (Fagan et al., J.
Biol. Chem.
275:26530-26537, 2000), gene transcription (Lewis, Annu. Rev. Immunol. 19:497-
521, 2001),
cell proliferation (Nunez et al., J. Physiol. 571.1, 57-73, 2006), and release
of cytokines
(Winslow et al., Curr. Opin. Immunol. 15:299-307, 2003). In some nonexcitable
cells, e.g., blood
cells, immune cells, hematopoietic cells, T lymphocytes and mast cells, SOC
influx occurs
through calcium release-activated calcium (CRAC) channels, a type of SOC
channel.
[0005] The calcium influx mechanism has been referred to as store-operated
calcium entry
(SOCE). Stromal interaction molecule (STIM) proteins are an essential
component of SOC
channel function, serving as the sensors for detecting the depletion of
calcium from intracellular
stores and for activating SOC channels.
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SUMMARY
100061 One aspect described herein is a process for the synthesis of compounds
of Formula (I):
(R2)õ
R.;')< RI 0 Si
0 N 0
1
N.-L,N
(R3), (0
or pharmaceutically acceptable salts thereof, wherein:
R1 is independently selected at each occurrence from hydrogen, halogen and C1-
C3 alkyl
optionally substituted with one or more substituents independently selected at
each
occurrence from halogen, -OR', -CN, -N(R')2 and -NO2;
R2 and R3 are independently selected at each occurrence from halogen and Ci-C3
alkyl
optionally substituted with one or more substituents independently selected at
each
occurrence from halogen, -OR', -CN, -N(R')2 and -NO2;
or, when both Rl are independently Ci-C3 alkyl, the two le groups are taken
together
with the atom to which they are attached to form a carbocycle;
n is 0, 1, 2 or 3;
m is 0, 1, 2, 3, 4, or 5; and
R' is independently selected at each occurrence from hydrogen; and CI-6 alkyl,
C2-6
alkenyl, and C2-6 alkynyl, each optionally substituted with one or more
substituents
independently selected at each occurrence from halogen, -CN, -NO2, -OH, -NH2,
and
OCH3;
wherein the process comprises contacting a compound of Formula (I-A)
(R2),
Ri 0
R?<
0 N
N
NH2 (I-A)
with a compound of Formula (I-B)
0
X
(R3)m (I-B)
in the presence of a tertiary amine base and an aprotic polar solvent, wherein
X is -Cl, -Br, -I, -
CN, -N3, -OCH3, -OCH2CH3, -006H5, -006H4-4-NO2, -0C(0)CH3, -0C(0)C6H5, -
0(S02)CH3,
or -0(S02)C6H4-4-CH3.
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[0007] In some embodiments, the tertiary amine base is selected from the group
consisting of
pyridine, triethylamine, triisopropyl amine, 2-tert-butyl-1,1,3,3-
tetramethylguanidine,
4-dimethylaminopyridine, N,N-diisopropylethylamine and N-methylmorpholine.
[0008] In some embodiments, the aprotic polar solvent is selected from the
group consisting of
chloroform, dichloromethane, and mixtures thereof.
[0009] In some embodiments, the compound of Formula (I-A)
(R2)n
R1?\
0 N
NH2 (I-A)
is synthesized by treating a compound of formula (LC)
(R2)n
RI JD
N
N R4
H (I-C)
with an acid, wherein R4 is selected from the group consisting of trityl, t-
butyl, t-butoxycarbonyl,
p-tolyl, benzoyl, acetyl and benzyl.
[0010] In some embodiments, the acid is selected from the group consisting of
trifluoroacetic
acid, sulfuric acid and hydrochloric acid.
[0011] In some embodiments, the compound of Formula (I-A)
(R2)n
R1 j)
R1?\
0 N
,Nri2 (I-A)
is synthesized by subjecting a compound of formula (I-C)
(R2)n
Ru0
N
N R4
H (I-C)
to a hydrogenation, wherein le is selected from the group consisting of
trityl, t-butyl, p-tolyl, and
benzyl.
[0012] In some embodiments, the compound of formula (I-C)
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(R2),
RizO
R12\
0 N
N R4
H (I-C)
is synthesized by coupling a compound of formula (I-D)
0 N
NR4
H (I-13)
and a compound of formula (I-E)
(R2)0
Ri 0
R;)<0
Br (I-E)
in the presence of a coupling catalyst
[0013] In some embodiments, the coupling catalyst is a palladium-based
catalyst. In some
embodiments, the palladium-based catalyst is selected from the group
consisting of Pd(PPh3)4,
Pd(dppf)C12 and PdC12(PPh3)4.
[0014] In some embodiments, the coupling is conducted at a temperature from
about 80 C to
about 90 C.
[0015] In some embodiments, the compound of formula (I-D)
BN
H (I-13)
is synthesized by treating a compound of formula (I-F)
R5,
N NR4
H (I-F)
with bis(pinacolato)diboron in the presence of a second palladium-based
catalyst, a base and a
polar solvent, wherein R5 is independently selected from a halogen, -
0(S02)C6H4-4-CH3,
and -0(S02)CH3.
[0016] In some embodiments, the second palladium-based catalyst is
Pd(dppf)C12.
[0017] In some embodiments, the base is potassium acetate.
[0018] In some embodiments, the compound of formula (I-F) is
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Br
N
and is synthesized from 2-amino-5-bromopyrazine
[0019] In some embodiments, the compound of formula (I-F) is a crystalline
solid.
[0020] In some embodiments, the compound of formula (I-B)
0
XI
(R3)rn (I-B)
is synthesized by treating a compound of formula (I-G)
0
HO 110
(R3)rn (I-G)
with an acyl halide preparation agent.
[0021] In some embodiments, the acyl halide preparation agent is selected from
the group
consisting of oxalyl chloride, thionyl chloride, phosphoryl chloride, and
phosphorus trichloride.
[0022] In some embodiments, R1 is independently selected at each occurrence
from hydrogen,
halogen and Ci-C3 alkyl optionally substituted with one or more substituents
independently
selected at each occurrence from halogen, -OH, -OCH3, -CN, -NH2, and -NO2; and
R2 and R3 are
independently selected at each occurrence from halogen and Ci-C3 alkyl
optionally substituted
with one or more substituents independently selected at each occurrence from
halogen, -OH, -
OCH3, -CN, -NH2, and -NO2.
[0023] One aspect described herein is a process for the synthesis of a
compound of Formula (II)
0 CI
F.- No N 0 CH3
N
(II)
or a pharmaceutically acceptable salt thereof, wherein the process comprises
contacting a
compound of Formula (II-A)
Fx0 CI
F 0 N
NH2 (II-A)
with a compound of Formula (II-B)
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0 CH3
CI tip
(II-B)
in the presence of a tertiary amine base and an aprotic polar solvent.
[0024] In some embodiments, the tertiary amine base is selected from the group
consisting of
pyridine, triethylamine, triisopropyl amine, 2-tert-butyl-1,1,3,3-
tetramethylguanidine,
4-dimethylaminopyridine, N,N-diisopropylethylamine and N-methylmorpholine.
[0025] In some embodiments, the aprotic polar solvent is selected from the
group consisting of
chloroform, dichloromethane, and mixtures thereof
[0026] In some embodiments, the compound of Formula (II-A)
F
0 CI
0 N
NH2 (ILA)
is synthesized by treating a compound of formula (MC)
0 CI
F N Ph
,k-Ph
N ph
(MC)
with an acid.
[0027] In some embodiments, the acid is selected from the group consisting of
trifluoroacetic
acid, sulfuric acid and hydrochloric acid.
[0028] In some embodiments, the compound of Formula (II-A)
0 N
N H2 (MA)
is synthesized by subjecting a compound of formula (TI-C)
CI
F* N Ph
A-Ph
N ph
to a hydrogenation
[0029] In some embodiments, the compound of formula (IT-C)
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0 CI
F\0 N Ph
IN ph
is synthesized by coupling a compound of formula (II-D)
0 N Ph
I\LA )<Ph
N Ph
(II-D)
and a compound of formula (II-E)
p CI
F2\
0 Br (II-E)
in the presence of a coupling catalyst.
[0030] In some embodiments, the coupling catalyst is a palladium-based
catalyst.
[0031] In some embodiments, the palladium-based catalyst is selected from the
group consisting
of Pd(PPh3)4, Pd(dppf)C12 and PdC12(PPh3)4.
[0032] In some embodiments, the coupling is conducted at a temperature from
about 80 C to
about 90 C.
[0033] In some embodiments, the compound of formula (II-D)
I\L 0 N Ph
A Ph
N Ph
(II-D)
is synthesized by treating a compound of formula (II-F)
Br Ph
)<Ph
N Ph
(II-F)
with bis(pinacolato)diboron in the presence of a second palladium-based
catalyst, a base and a
polar solvent.
[0034] In some embodiments, the second palladium-based catalyst is
Pd(dppf)C12.
[0035] In some embodiments, the base is potassium acetate
[0036] In some embodiments, the polar solvent is 1,4-dioxane.
[0037] In some embodiments, the compound of formula (II-F)
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Bry-,1\1 Ph
)<Ph
N Ph
(II-F)
is synthesized from 2-amino-5-bromopyrazine.
[0038] In some embodiments, the compound of formula (II-F) is a crystalline
solid.
[0039] In some embodiments, the compound of formula (II-B)
0
CI
1.1
(II-B)
is formed by treating a compound of formula (II-G)
0
HO
(II-G)
with an acyl halide preparation agent.
[0040] In some embodiments, the acyl halide preparation agent is selected from
the group
consisting of oxalyl chloride, thionyl chloride, phosphoryl chloride, and
phosphorus trichloride.
INCORPORATION BY REFERENCE
[0041] All publications, patents, and patent applications mentioned in this
specification are
herein incorporated by reference to the same extent as if each individual
publication, patent, or
patent application was specifically and individually named as incorporated by
reference.
DETAILED DESCRIPTION
Definitions
[0042] Unless defined otherwise, all technical and scientific terms used
herein have the same
meaning as is commonly understood in the field to which the claimed subject
matter belongs. In
the event that there is a plurality of definitions for terms herein, those in
this section prevail. All
patents, patent applications, publications and published nucleotide and amino
acid sequences
(e.g., sequences available in GenBank or other databases) referred to herein
are incorporated by
reference. Where reference is made to a URL or other such identifier or
address, it is understood
that such identifiers can change and particular information on the internet
can come and go, but
equivalent information is found by searching the internet. Reference thereto
evidences the
availability and public dissemination of such information.
[0043] It is to be understood that the foregoing general description and the
following detailed
description are exemplary and explanatory only and are not restrictive of any
subject matter
claimed. In this application, the use of the singular includes the plural
unless specifically stated
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otherwise. It must be noted that, as used in the specification and the
appended claims, the
singular forms "a," "an" and "the" include plural referents unless the context
clearly dictates
otherwise. In this application, the use of "or" means "and/or" unless stated
otherwise.
Furthermore, use of the term "including" as well as other forms, such as
"include", "includes,"
and "included," is not limiting.
[0044] The section headings used herein are for organizational purposes only
and are not to be
construed as limiting the subject matter described.
[0045] Definition of standard chemistry terms are found in reference works,
including but not
limited to, Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4TH ED." Vols. A
(2000) and B (2001), Plenum Press, New York. Unless otherwise indicated,
conventional
methods of mass spectroscopy, NM_R, HPLC, protein chemistry, biochemistry,
recombinant
DNA techniques and pharmacology, within the skill of the art are employed.
[0046] The term "CRAC channel inhibitor" refers to inhibitors that suppress
calcium release
activated channel (CRAC), which are specialized plasma membrane Ca' ion
channels that
slowly replenish depleted levels of calcium in the endoplasmic reticulum.
[0047] The terms "inhibits", "inhibiting", or "inhibitor" of CRAC channel
activity, as used
herein, refer to inhibition of store operated calcium channel activity or
calcium release activated
calcium channel activity.
[0048] As used herein, Ci-Cx includes CI-C2, Ci-C3 . . . Ci-C. Ci-Cx refers to
the number of
carbon atoms that make up the moiety to which it designates (excluding
optional substituents).
[0049] An "alkyl" group refers to an aliphatic hydrocarbon group. The alkyl
groups may or may
not include units of unsaturation. The alkyl moiety may be a "saturated alkyl"
group, which
means that it does not contain any units of unsaturation (i.e. a carbon-carbon
double bond or a
carbon-carbon triple bond). The alkyl group may also be an "unsaturated alkyl"
moiety, which
means that it contains at least one unit of unsaturation. The alkyl moiety,
whether saturated or
unsaturated, may be branched, straight chain, or cyclic.
[0050] The "alkyl" group may have 1 to 6 carbon atoms (whenever it appears
herein, a numerical
range such as "1 to 6" refers to each integer in the given range; e.g., "1 to
6 carbon atoms" means
that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon
atoms, etc., up to
and including 6 carbon atoms, although the present definition also covers the
occurrence of the
term "alkyl" where no numerical range is designated). The alkyl group of the
compounds
described herein may be designated as "C1-C6 alkyl" or similar designations.
By way of example
only, "Ci-C6 alkyl" indicates that there are one to six carbon atoms in the
alkyl chain, i.e., the
alkyl chain is selected from the group consisting of methyl, ethyl, n-propyl,
iso-propyl, n-butyl,
iso-butyl, sec-butyl, t-butyl, n-pentyl, iso-pentyl, neo-pentyl, hexyl, propen-
3-y1 (allyl),
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cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl.
Alkyl groups can
be substituted or unsubstituted. Depending on the structure, an alkyl group
can be a monoradical
or a diradical (i.e., an alkylene group).
[0051] The term "alkenyl" refers to a type of alkyl group in which the first
two atoms of the alkyl
group form a double bond that is not part of an aromatic group. That is, an
alkenyl group begins
with the atoms ¨C(R)=CR2, wherein R refers to the remaining portions of the
alkenyl group,
which may be the same or different. Non-limiting examples of an alkenyl group
include
CH=CH2, ¨C(CH3)=CH2, ¨CH=CHCH3, ¨CH=C(CH3)2 and ¨C(CH3)=CHCH3. The
alkenyl moiety may be branched, straight chain, or cyclic (in which case, it
would also be known
as a "cycloalkenyl" group). Alkenyl groups may have 2 to 6 carbons. Alkenyl
groups can be
substituted or unsubstituted. Depending on the structure, an alkenyl group can
be a monoradical
or a diradical (i.e., an alkenylene group).
[0052] The term "alkynyl" refers to a type of alkyl group in which the first
two atoms of the
alkyl group form a triple bond. That is, an alkynyl group begins with the
atoms ¨CC¨R,
wherein R refers to the remaining portions of the alkynyl group. Non-limiting
examples of an
alkynyl group include ¨CCH, ¨CCCH3, ¨CCCH2CH3 and ¨CCCH2CH2CH3. The "R"
portion of the alkynyl moiety may be branched, straight chain, or cyclic. An
alkynyl group can
have 2 to 6 carbons. Alkynyl groups can be substituted or unsubstituted.
Depending on the
structure, an alkynyl group can be a monoradical or a diradical (i.e., an
alkynylene group).
[0053] "Carbocycle" refers to saturated, unsaturated or aromatic rings in
which each atom of the
ring is carbon. Carbocycle may be monocyclic or polycyclic and may include 3-
to 10-membered
monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered
bridged rings. Each
ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and
aromatic rings. In
some embodiments, the carbocycle is an aryl. In some embodiments, the
carbocycle is a
cycloalkyl. In some embodiments, the carbocycle is a cycloalkenyl. In an
exemplary
embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or
unsaturated ring, e.g.,
cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated,
unsaturated and
aromatic bicyclic rings, as valence permits, is included in the definition of
carbocyclic.
Exemplary carbocycles include cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cyclohexenyl,
adamantyl, phenyl, indanyl, and naphthyl. Unless stated otherwise specifically
in the
specification, a carbocycle is optionally substituted by one or more
substituents such as those
substituents described herein.
[0054] The term "trityl" refers to a triphenylmethyl group. In the art,
"trityl" protecting groups
are covalently attached to heteroatoms, and are used to protect heteroatoms
from undesired
chemical reactions.
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[0055] The term "halo" or, alternatively, "halogen" means fluoro, chloro,
bromo, or iodo.
[0056] The compounds disclosed herein, in some embodiments, are used in
different enriched
isotopic forms, e.g., enriched in the content of 2H, 3H, 11C, 13C and/or "C.
In one particular
embodiment, a compound described herein is deuterated in at least one
position. Such deuterated
forms can be made by the procedure described in U.S. Patent Nos. 5,846,514 and
6,334,997. As
described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve
the metabolic
stability and or efficacy, thus increasing the duration of action of drugs.
[0057] Unless otherwise stated, structures depicted herein are intended to
include compounds
which differ only in the presence of one or more isotopically enriched atoms.
For example,
compounds having the present structures except for the replacement of a
hydrogen by a
deuterium or tritium, or the replacement of a carbon by 13C- or 14C-enriched
carbon are within
the scope of the present disclosure.
[0058] The compounds of the present disclosure optionally contain unnatural
proportions of
atomic isotopes at one or more atoms that constitute such compounds. For
example, the
compounds may be labeled with isotopes, such as deuterium (2H), tritium (3H),
iodine-125 (1251)
or carbon-14 (14C). Isotopic substitution with 2H, 11C, 13C, 14C, 15C, 12N,
13N, 15N, 16N, 160, 170,
14F, 15F, 16F, 17F, 18F, 33s, 34s, 35s, 36,-%
S 350, 370, 79Br, 81Br, 1251 are all contemplated. All isotopic
variations of the compounds described herein, whether radioactive or not, are
encompassed
within the scope of the present disclosure.
[0059] In certain embodiments, the compounds disclosed herein have some or all
of the 1H atoms
replaced with 2H atoms. The methods of synthesis for deuterium-containing
compounds are
known in the art and include, by way of non-limiting example only, the
following synthetic
methods.
[0060] Deuterium substituted compounds are synthesized using various methods
such as
described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and
Applications of
Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm.
Des., 2000;
6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of
Radiolabeled Compounds
via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and
Evans, E. Anthony.
Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.
[0061] Deuterated starting materials are readily available and are subjected
to the synthetic
methods described herein to provide for the synthesis of deuterium-containing
compounds. Large
numbers of deuterium-containing reagents and building blocks are available
commercially from
chemical vendors, such as Aldrich Chemical Co.
[0062] Deuterium-transfer reagents suitable for use in nucleophilic
substitution reactions, such as
iodomethane-d3 (CD3I), are readily available and may be employed to transfer a
deuterium-
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substituted carbon atom under nucleophilic substitution reaction conditions to
the reaction
substrate. The use of CD3I is illustrated, by way of example only, in the
reaction schemes below.
rõ,OH CD3I re=D
R¨ I ¨1- R-1 I nD
base D
CD3I 111
R QyNH
base ND
nD
0 0 D
[0063] Deuterium-transfer reagents, such as lithium aluminum deuteride
(LiAlD4), are employed
to transfer deuterium under reducing conditions to the reaction substrate. The
use of LiAlD4 is
illustrated, by way of example only, in the reaction schemes below.
R, L1AID4 R H2 R.0O2H L1AI04 D D
CN A X LIAID4 D R'
D D R OH RXOH
[0064] Deuterium gas and palladium catalysts are employed to reduce
unsaturated carbon-carbon
linkages and to perform a reductive substitution of aryl carbon-halogen bonds
as illustrated, by
way of example only, in the reaction schemes below.
Br_rk,
D2 D2
H H D
R" R" R' R" R' R" R'
Pd-C
Pd -C Et0Ac Et0Ac H D
40 02
R' R" R'
Pd-C
R" Et0Ac D D
[0065] The term "tertiary amine base" refers to a nitrogen base that has
exceeded its bonding
valence. In the art, "tertiary amine bases" are also referred to as "bulky" or
"non-nucleophilic"
base, as they are less susceptible to nucleophilic attack. Examples of
"tertiary amine base" as
used herein include, but are not limited to, pyridine, triethylamine,
triisopropyl amine,
tributylamine, 2-tert-butyl-1,1,3,3-tetramethylguanidine, 4-
dimethylaminopyridine, N,N-
diisopropylethylamine, 1,8-diazabicycloundec-7-ene, 1,5-diazabicyclo(4.3.0)non-
5-ene, 2,6-di-
tert-butylpyridine, 1,8-bis(dimethylamino)naphthalene, 2,6-lutidine, 1,1,3,3-
tetramethylguanidine, 2,2,6,6-tetramethylpiperidine, 2,4,6-trimethylpyridine,
1,4-
diazabicyclo(2.2.2)octane, N,N-dicyclohexylmethylamine, quinuclidine,
pempidine, 1,5,7-
triazabicyclo(4.4.0)dec-5-ene, 7-methy1-1,5,7-triazabicyclo(4.4.0)dec-5-ene,
3,3,6,9,9-
pentamethy1-2,10-diazabicyclo-(4.4.0)dec-1-ene, and N-methylmorpholine.
[0066] The term "aprotic polar solvent" refers to a solvent that lacks an
acidic, or an
exchangeable, hydrogen atom. Intrinsically, an "aprotic polar solvent" does
not facilitate
hydrogen bonding interactions, and facilitates SN2-type reactions. Examples of
"aprotic polar
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solvent" as used herein include, but are not limited to, chloroform, N-
methylpyrrolidone,
tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, acetone, N,N-
dimethylformamide
(dimethylformamide, or DMF), N,N-dimethylacetamide (dimethylacetamide, or
DMA),
acetonitrile (or MeCN), dimethyl sulfoxide (or DMSO), propylene carbonate, 1,4-
dioxane (or
dioxane), and dichloromethane (or DCM). The term "aprotic polar solvent" also
encompasses
mixtures, or combinations, of two or more aprotic polar solvents.
[0067] The term "protic polar solvent" refers to a solvent that has a labile,
or an acidic, or an
exchangeable, hydrogen atom. "Protic polar solvent" facilitate hydrogen
bonding interactions.
Examples of "protic polar solvent" as used herein include, but are not limited
to, water, acetic
acid, formic acid, methanol, ethanol, n-propanol, and t-butanol. The term
"protic polar solvent"
also encompasses mixtures, or combinations, of two or more protic polar
solvents.
[0068] The term "polar solvent" refers to an aprotic polar solvent, or a
protic polar solvent, or
combinations thereof.
[0069] The term "acid" refers to a molecule that has a labile, or acidic,
hydrogen atom. Examples
of "acid" as used herein include, but are not limited to, trifluoroacetic acid
(or TFA), 2, 2, 2-
trifluoroethanol, sulfuric acid, nitric acid, hydrofluoric acid, hydrobromic
acid, hydroiodic acid,
triflic acid (or trifluoromethanesulfonic acid), perchloric acid, phosphoric
acid, chloric acid,
methanesulfonic acid, p-toluenesulfonic acid, acetic acid, formic acid, and
hydrochloric acid.
Other examples of "acid" as used herein include, but are not limited to,
molecules with a pKa
measured in water less than about 5.5. The term "acid" also encompasses
mixtures, or
combinations, of two or more acids.
[0070] The term "base" refers to a molecule that can extract a hydrogen atom
from another
molecule. Examples of "base" as used herein include, but are not limited to,
an alkali metal
hydroxide, an alkali metal carbonate, an alkali metal bicarbonate, an alkali
metal alkoxide, an
alkali metal carboxylate, an alkali metal oxide, an alkali metal fluoride, an
alkaline earth metal
hydroxide, an alkaline earth metal carbonate, an alkaline earth metal
bicarbonate, an alkaline
earth metal alkoxide, an alkaline earth metal carboxylate, an alkaline earth
metal oxide, a primary
amine, a secondary amine, a tertiary amine, a lanthanide hydroxide, a
lanthanide carbonate, a
lanthanide bicarbonate, a lanthanide alkoxide, a lanthanide carboxylate, a
lanthanide oxide, and
combinations thereof. Representative, but not limiting, examples of "base" as
used herein include
lithium hydroxide, sodium hydroxide, potassium hydroxide, ammonium hydroxide,
potassium
acetate (KOAc), sodium acetate (Na0Ac), tripotassium phosphate, sodium
butoxide, potassium
butoxide, potassium t-butoxide, sodium carbonate, potassium carbonate, cesium
carbonate,
cesium fluoride, sodium bicarbonate, potassium bicarbonate, calcium hydroxide,
and
triethylamine.
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[0071] The term "hydrogenation" refers to a chemical reaction between
molecular hydrogen and
a reactant in the presence of a catalyst, such as, but not limited to a
composition comprising
nickel, palladium, platinum, rhodium, ruthenium, or combinations thereof A
"hydrogenation"
reaction is commonly utilized to reduce or saturate organic compounds via the
addition of
hydrogen atom pairs.
[0072] The term "metal reduction" refers to a reduction where an alkali metal
or low valent
transition metal in a suitable solvent or solvent mixture adds the equivalent
of hydrogen, two
protons and two electrons, to a substrate molecule, resulting either in
reductive cleavage of a
single bond, or reduction of a multiple bond. In certain, but not all, cases a
"metal reduction" as
used herein is referred to as a "dissolving metal reduction" in the art.
[0073] The term "coupling reaction" refers to a chemical reaction where two
fragments combine
with the aid of a metal catalyst, or "coupling catalyst". Examples of
"coupling reactions" as used
herein include, but are not limited to, reactions known in the art as
"Suzuki", "Negishi", "Stille",
or "Liebeskind-Srogl" coupling reactions. Examples of "coupling catalysts" as
used herein
include, but are not limited, to a composition comprising copper, palladium,
nickel, iron, or
combinations thereof. The term "palladium-based catalyst" refers to a coupling
catalyst
comprising palladium. Examples of a "palladium-based catalyst" as used herein
include, but are
not limited to, Pd(PPh3)4, Pd(OAc)2, Pd(dppf)C12 (where "dppf' is 1,1'-
bis(diphenylphosphino)ferrocene), Pd(dtbpf)C12 (where "dtbpf' is 1,1'-bis(di-
tert-
butylphosphino)ferrocene, Pd(dba)2 (bis(dibenzylideneacetone)palladium(0)),
Pd2(dba)3 (tris-
(dibenzylideneacetone)palladium(0)), Pd(PCy3)2 (where "Cy" is cyclohexyl),
Pd(dppe)C12
(where "dppe" is 1,2-bis(diphenylphosphino)ethane), Pd(t-Bu3P)2, PdC12[P(o-
To1)3]2, benzylbis-
(triphenylphosphine)palladium(II) chloride, (A-Phos)2C12Pd, Na2PdC14,
Na2PdC14/DTBPPS
(where "DTBPPS" is 3-(di-tert-butylphosphonium)propane sulfonate), and
PdC12(PPh3)4.
Representative, but not limiting, examples of (A-Phos)2C12Pd palladium-based
catalysts are
disclosed in the Journal of Organic Chemistry 2007, 72, pages 5104-5112, by
Guram et al.
[0074] The term "acyl halide preparation agent" refers to a chemical reagent
that is used to
convert a carboxylic acid or a carboxylic acid derivative, including, but not
limited to, a
carboxylic acid salt, to a carboxylic acid halide, or acyl halide. In the case
where the halide is
chloride, the "acyl halide preparation agent" is an "acyl chloride preparation
agent". Examples of
"acyl chloride preparation agents", as used herein include, but are not
limited to oxalyl chloride,
thionyl chloride, phosphoryl chloride, phosphorus trichloride, methanesulfonyl
chloride,
trichloromethanesulfonyl chloride, tert-butyl hypochlorite, dichloromethyl
methyl ether,
methoxyacetyl chloride, cyanuric chloride, N-chlorosuccinamide, N-
chlorophthalimide, and
trimethylsilyl chloride. In the case where the halide is bromide, the "acyl
halide preparation
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agent" is an "acyl bromide preparation agent". Examples of "acyl bromide
preparation agents",
as used herein include, but are not limited to phosphorus tribromide,
methanesulfonyl bromide,
cyanuric bromide, triphenylphosphine/N-bromosuccinamide, and
triphenylphosphine/bromine.
[0075] Compounds described herein may be formed as, and/or used as,
pharmaceutically
acceptable salts. The type of pharmaceutical acceptable salts, include, but
are not limited to: (1)
acid addition salts, formed by reacting the free base form of the compound
with a
pharmaceutically acceptable: inorganic acid, such as, for example,
hydrochloric acid,
hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphoric acid, and the
like; or with an
organic acid, such as, for example, acetic acid, propionic acid, hexanoic
acid,
cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic
acid, succinic acid,
malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid,
citric acid, benzoic acid,
3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,
methanesulfonic acid,
ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid,
benzenesulfonic
acid, toluenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-
[2.2.2]oct-2-ene-1-
carboxylic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-
carboxylic acid), 3-
phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl
sulfuric acid, gluconic
acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid,
muconic acid, butyric
acid, phenylacetic acid, phenylbutyric acid, valproic acid, and the like; (2)
salts formed when an
acidic proton present in the parent compound is replaced by a metal ion, e.g.,
an alkali metal ion
(e.g. lithium, sodium, potassium), an alkaline earth ion (e.g. magnesium, or
calcium), or an
aluminum ion. In some cases, compounds described herein may coordinate with an
organic base,
such as, but not limited to, ethanolamine, diethanolamine, triethanolamine,
tromethamine, N-
methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine. In other
cases,
compounds described herein may form salts with amino acids such as, but not
limited to,
arginine, lysine, and the like. Acceptable inorganic bases used to form salts
with compounds that
include an acidic proton, include, but are not limited to, aluminum hydroxide,
calcium hydroxide,
potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.
[0076] It should be understood that a reference to a pharmaceutically
acceptable salt includes the
solvent addition forms or crystal forms thereof, particularly solvates or
polymorphs. Solvates
contain either stoichiometric or non-stoichiometric amounts of a solvent, and
may be formed
during the process of crystallization with pharmaceutically acceptable
solvents such as water,
ethanol, and the like. Hydrates are formed when the solvent is water, or
alcoholates are formed
when the solvent is alcohol. Solvates of compounds described herein can be
conveniently
prepared or formed during the processes described herein. In addition, the
compounds provided
herein can exist in unsolvated as well as solvated forms. In general, the
solvated forms are
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considered equivalent to the unsolvated forms for the purposes of the
compounds and methods
provided herein.
[0077] In addition, compounds described herein include crystalline forms, also
known as
polymorphs. Polymorphs include the different crystal packing arrangements of
the same
elemental composition of a compound. Polymorphs usually have different X-ray
diffraction
patterns, melting points, density, hardness, crystal shape, optical
properties, stability, and
solubility. Various factors such as the recrystallization solvent, rate of
crystallization, and storage
temperature may cause a single crystal form to dominate.
[0078] The synthetic method disclosed herein is an method for producing CRAC
channel
inhibitors. In some embodiments, this method produces kilogram quantities. The
methods may
improve previous synthetic routes by eliminating the presence of multiple
undesirable impurities.
Process of synthesizing CRAC channel inhibitors
[0079] One aspect described herein is a process of synthesizing CRAC channel
inhibitors. In
some embodiments, the CRAC channel inhibitors are compounds of Formula (I):
(R2),
Ri 0
0 N 0
1
NN
(R3), (I),
or pharmaceutically acceptable salts thereof, wherein:
Rl is independently selected at each occurrence from hydrogen, halogen and Ci-
C3 alkyl
optionally substituted with one or more substituents independently selected at
each
occurrence from halogen, -OR', -CN, -N(R')2 and -NO2;
R2 and IV are independently selected at each occurrence from halogen and Ci-C3
alkyl
optionally substituted with one or more substituents independently selected at
each
occurrence from halogen, -OR', -CN, -N(R')2 and -NO2;
or, when both Rl are independently Ci-C3 alkyl, the two Rl groups are taken
together
with the atom to which they are attached to form a carbocycle;
n is 0, 1, 2 or 3;
m is 0, 1, 2, 3, 4, or 5; and
R' is independently selected at each occurrence from hydrogen; and C1-6 alkyl,
C2.6 alkenyl, and
C2-6 alkynyl, each optionally substituted with one or more substituents
independently selected at
each occurrence from halogen, -CN, -NO2, -OH, -NH2, and OCH3.
[0080] In some embodiments, R1 is independently selected at each occurrence
from hydrogen,
halogen and Ci-C3 alkyl optionally substituted with one or more substituents
independently
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selected at each occurrence from halogen, -OH, -OCH3, -CN, -NH2, and -NO2; and
R2 and R3 are
independently selected at each occurrence from halogen and Ci-C3 alkyl
optionally substituted
with one or more substituents independently selected at each occurrence from
halogen, -OH, -
OCH3, -CN, -NH2, and -NO2.
[0081] One aspect described herein is a process of synthesizing CRAC channel
inhibitors,
wherein the CRAC channel inhibitors are compounds of Formulas (IA), (IB),
(IC), (ID), (1E),
(IF), or (IG):
R2
R2 R2
Ri 0
Ri% IRa<c),
N 0 N 0
N m110 R2 N
Ito
(R3). (IA), (R3)m (m),
(R2)n
Ri
(R2)n
R1'\o Ri 0
N 0 R3
NN 401 0 N 0 R3
N 11101
R3 R3
R3 (IC), R3 R3 (ID),
R2
R2
Ri 0 R1'\0
N 0 R3
N 0 R3
1
R2 N
1101 R3
R3 (IF), R3 (IF),
R2
R1,z0
R1-'\0
N 0 R3
NN
R3 (IG), or a salt of any one thereof.
In certain embodiments, for a compound, or salt, of any one of Formulas (I),
(IA), (B3), (IC),
(ID), (1E), (IF), and (IG), Rl is independently selected at each occurrence
from hydrogen,
halogen and Ci-C3 alkyl optionally substituted with one or more substituents
independently
selected at each occurrence from halogen, -OR', -CN, -N(R')2 and -NO2; R2 and
R3 are
independently selected at each occurrence from halogen and Ci-C3 alkyl
optionally substituted
with one or more substituents independently selected at each occurrence from
halogen, -OR', -
CN, -N(R')2 and -NO2; wherein R' is independently selected at each occurrence
from hydrogen;
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and C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each optionally substituted
with one or more
substituents independently selected at each occurrence from halogen, -CN, -
NO2, -OH, -NH2, and
OCH3.
[0082] In some embodiments, R1 is independently selected at each occurrence
from hydrogen,
halogen and Ci-C3 alkyl optionally substituted with one or more substituents
independently
selected at each occurrence from halogen, -OH, -OCH3, -CN, -NH2, and -NO2; and
R2 and R3 are
independently selected at each occurrence from halogen and Ci-C3 alkyl
optionally substituted
with one or more substituents independently selected at each occurrence from
halogen, -OH, -
OCH3, -CN, -NH2, and -NO2.
[0083] In certain embodiments, for a compound or salt of any one of Formulas
(I), (IA), (113),
(IC), and (ID), n is 0, 1, 2 or 3. In certain embodiments, for a compound or
salt of any one of
Formulas (I), (IA), (B3), (IC), and (ID), n is 0, 1, or 2. In certain
embodiments, for a compound or
salt of any one of Formulas (I), (IA), (B3), (IC), and (ID), n is 0 or 1. In
certain embodiments, for
a compound or salt of any one of Formulas (I), (IA), (113), (IC), and (ID), n
is 1. In embodiments,
for a compound, or salt, of any one of Formulas (I), (IA), (B3), (IC), (ID),
(1E), (IF), and (IG),
where n is 0, 1, or 2, the open position(s), position(s) without R2 on the
aromatic ring, is(are)
occupied by hydrogen.
[0084] In certain embodiments, for a compound or salt of any one of Formulas
(I), (IA), and
(113), m is 0, 1, 2, 3, or 4. In certain embodiments, for a compound or salt
of any one of Formulas
(I), (IA), and (IB), m is 0, 1, 2, or 3. In certain embodiments, for a
compound or salt of any one
of Formulas (I), (IA), and (B3), m is 0, 1, or 2. In certain embodiments, for
a compound or salt of
any one of Formulas (I), (IA), and (B3), m is 2. In embodiments, for a
compound, or salt, of any
one of Formulas (I), (IA), (B3), (IC), (ID), (IE), (IF), and (IG), where m is
0, 1, 2, 3, or 4, the
open position(s), position(s) without R3 on the aromatic ring, is(are)
occupied by hydrogen.
[0085] In certain embodiments, for a compound, or salt, of any one of Formulas
(I), (1E), (IF),
and (IG), n is 1 or 2, m is 2 or 3, and the open positions, positions that are
not substituted with R2
or R3, are occupied by hydrogen, according to standard conventions applicable
to structural
drawings. In certain embodiments, for a compound, or salt, of any one of
Formulas (I) and (IG),
n is 1, m is 2, and the open positions, positions that are not substituted
with R2 or R3, are
occupied by hydrogen, according to standard conventions applicable to
structural drawings.
[0086] In certain embodiments, for a compound or salt of any one of Formulas
(I), (IA), (113),
(IC), (ID), (1E), (IF), and (IG), R' is independently selected at each
occurrence from hydrogen;
and C1-6 alkyl, C2.6 alkenyl, and C2.6 alkynyl, each optionally substituted
with one or more
substituents independently selected at each occurrence from halogen, -CN, -
NO2, -OH, -NH2, and
OCH3.
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[0087] In some embodiments, for a compound, or salt, of Formula (IG), le and
R2 are
independently at each occurrence a halogen and R3 is independently at each
occurrence a halogen
or a Ci-C3 alkyl. In some embodiments, for a compound, or salt, of Formula
(IG), both le are
fluoro, R2 is a halogen and R3 is independently at each occurrence a halogen
or a Ci-C3 alkyl. In
some embodiments, for a compound, or salt, of Formula (IG), both R1 are
fluoro, R2 is chloro or
fluoro, and R3 is independently at each occurrence a halogen or a Ci-C3 alkyl.
In some
embodiments, for a compound, or salt, of Formula (IG), both R1 are fluoro, R2
is chloro or fluoro,
and R3 is independently at each occurrence a halogen, methyl, or ethyl. In
some embodiments,
for a compound, or salt, of Formula (IG), both Rl are fluoro, R2 is chloro or
fluoro, and R3 is
independently at each occurrence a halogen or methyl. In some embodiments, for
a compound, or
salt, of Formula (IG), both RI- are fluoro, R2 is chloro or fluoro, and R3 is
independently at each
occurrence chloro, fluoro, or methyl. In some embodiments, for a compound, or
salt, of Formula
(IG), both Rl are fluoro, R2 is chloro, and R3 is independently at each
occurrence chloro, fluoro,
or methyl. In some embodiments, for a compound, or salt, of Formula (IG), both
R1 are fluoro,
R2 is chloro, and R3 is independently at each occurrence fluoro or methyl. In
some embodiments,
for a compound, or salt, of Formula (IG), both Rl are fluoro, R2 is chloro,
one of R3 is fluoro, and
one of R3 is methyl.
[0088] One aspect described herein is a process of synthesizing CRAC channel
inhibitors. In
some embodiments, the CRAC channel inhibitors are compounds of Formula (I),
(IA), (B3), (IC),
(ID), (1E), (IF), or (IG):
wherein the process comprises contacting a compound of Formula (I-A):
(R2),
Ri
N
NH2 (I-A)
with a compound of Formula (I-B):
0
X
( R3) m (I-B)
in the presence of a tertiary amine base and an aprotic polar solvent, wherein
X is -Cl, -Br, -I, -
CN, -N3, -OCH3, -OCH2CH3, -006H5, -006H4-4-NO2, -0C(0)CH3, -0C(0)C6H5, -
0(S02)CH3,
or -0(802)C6H4-4-CH3.
[0089] In some embodiments, the tertiary amine base is selected from the group
consisting of
pyridine, triethylamine, triisopropyl amine, tributylamine, 2-tert-buty1-
1,1,3,3-
tetramethylguanidine, 4-dimethylaminopyridine, NN-diisopropylethylamine, 1,8-
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diazabicycloundec-7-ene, 1,5-diazabicyclo(4.3.0)non-5-ene, 2,6-di-tert-
butylpyridine, 1,8-
bis(dimethylamino)naphthalene, 2,6-lutidine, 1,1,3,3-tetramethylguanidine,
2,2,6,6-
tetramethylpiperidine, 2,4,6-trimethylpyridine, 1,4-diazabicyclo(2.2.2)octane,
N,N-
dicyclohexylmethylamine, quinuclidine, pempidine, 1,5,7-
triazabicyclo(4.4.0)dec-5-ene, 7-
methy1-1,5,7-triazabicyclo(4.4.0)dec-5-ene, 3,3,6,9,9-pentamethy1-2,10-
diazabicyclo-(4.4.0)dec-
1-ene, and N-methylmorpholine. In some embodiments, the tertiary amine base is
selected from
the group consisting of pyridine, triethylamine, triisopropyl amine, 2-tent-
buty1-1,1,3,3-
tetramethylguanidine, 4-dimethylaminopyridine, N, N-diisopropylethylamine and
N-
methylmorpholine. In some embodiments, the tertiary amine base is pyridine.
[0090] In some embodiments, the aprotic polar solvent is selected from the
group consisting of
chloroform, N-methylpyrrolidone, tetrahydrofuran, ethyl acetate, acetone,
dimethylformamide,
dimethylacetamide, acetonitrile, dimethyl sulfoxide, propylene carbonate,
dichloromethane, and
mixtures thereof. In some embodiments, the aprotic polar solvent is selected
from the group
consisting of chloroform, dichloromethane, and mixtures thereof. In some
embodiments, the
aprotic polar solvent is dichloromethane.
[0091] In some embodiments, the compound of Formula (I-A):
(R2),
Ri
N
NH2 (I-A)
is synthesized by treating a compound of formula (I-C):
R1?\
0 N
N /,LN, R4
H (I-C)
with an acid, wherein R4 is selected from the group consisting of trityl, t-
butyl, t-butoxycarbonyl,
p-tolyl, benzoyl, acetyl and benzyl.
[0092] In some embodiments, the acid is selected from the group consisting of
trifluoroacetic
acid, 2, 2, 2-trifluoroethanol, sulfuric acid, nitric acid, hydrofluoric acid,
hydrobromic acid,
hydroiodic acid, triflic acid, perchloric acid, phosphoric acid, chloric acid,
methanesulfonic acid,
p-toluenesulfonic acid, acetic acid, formic acid, and hydrochloric acid. In
some embodiments, the
acid is selected from the group consisting of trifluoroacetic acid, 2, 2, 2-
trifluoroethanol, sulfuric
acid, and hydrochloric acid. In some embodiments, the acid is hydrochloric
acid.
[0093] In some embodiments, the compound of Formula (I-A):
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(R2),
R1?\
0 N
1
NH 2 (I-A)
is synthesized by subjecting a compound of formula (I-C):
Ri
R1'\
0 N
1
õ R4
H (I-C)
to a hydrogenation or metal reduction, wherein le is selected from the group
consisting of trityl,
t-butyl, p-tolyl, benzoyl, acetyl and benzyl. In some embodiments, R4 is
selected from the group
consisting of trityl, t-butyl, p-tolyl, and benzyl. In some embodiments, R4 is
selected from the
group consisting of trityl and benzyl. In some embodiments, R4 is benzyl. In
some embodiments,
R4 is trityl.
[0094] In some embodiments, the hydrogenation uses a metal catalyst selected
from the group
consisting of Ni, Raney Ni, Pd/C, Degussa type catalyst, Pt/C, and Pd(OAc)2.
In some
embodiments, the hydrogenation uses a metal catalyst selected from the group
consisting of Ni,
Raney Ni, and Pd/C. In some embodiments, the hydrogenation uses a metal
catalyst selected
from the group consisting of Ni or Raney Ni. In some embodiments, the
hydrogenation catalyst is
Ni. In some embodiments, the hydrogenation catalyst is Raney Ni.
[0095] In some embodiments, the metal reduction uses a metal selected from the
group
consisting of lithium, sodium, and potassium, and the metal reduction
optionally uses a catalyst.
In some embodiments the catalyst is naphthalene. In some embodiments, the
metal reduction
uses a metal that is lithium and a catalyst that is naphthalene.
[0096] In some embodiments, the compound of formula (I-C):
Ri 0
0 N
1
N R4
(I-C)
is synthesized by coupling a compound of formula (I-D):
0
0 .rk'N
1
NAN,R4
(I-D)
and a compound of formula (I-E):
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)n
RijNo) .. (R2
Ri'
Br (I-E)
in the presence of a coupling catalyst.
[0097] In some embodiments, the compound of formula (I-C) is synthesized by
coupling a
compound of formula (I-D) and a compound of formula (I-E) in the presence of a
coupling
catalyst, a base, and a polar solvent.
[0098] In some embodiments, the compound of formula (I-C):
(R2)n
R1?\
0 N
N R4
H (I-C)
is synthesized by coupling a compound of formula (I-D):
HR
HOB ,N
N , R4
H
and a compound of formula (I-E):
(R2)n
RI 0 40
Br o_E)
in the presence of a coupling catalyst.
[0099] In some embodiments, the compound of formula (I-C) is synthesized by
coupling a
compound of formula (I-D-a) and a compound of formula (I-E) in the presence of
a coupling
catalyst, a base, and a polar solvent.
[0100] In some embodiments, the coupling catalyst is a palladium-based
catalyst. In some
embodiments, the palladium-based catalyst is selected from the group
consisting of Pd(PPh3)4,
Pd(OAc)2, Pd(dppf)C12, Pd(dtbpf)C12, Pd(dba)2, Pd(PCy3)2, Pd(dppe)C12, Pd(t-
Bu3P)2, PdC12[P(o-
To1)3]2, benzylbis(triphenylphosphine)palladium(II) chloride, (A-Phos)2C12Pd,
Na2PdC14, SPhos
(2-(2',6"-dimethoxybiphenyl)dicyclohexylphosphine) and PdC12(PPh3)4. In some
embodiments,
the palladium-based catalyst is selected from the group consisting of
Pd(PPh3)4, Pd(dppf)C12 and
PdC12(PPh3)4. In some embodiments, the palladium-based catalyst is Pd(PPh3)4.
[0101] In some embodiments, the base is selected from the group consisting of
lithium
hydroxide, sodium hydroxide, potassium hydroxide, ammonium hydroxide,
potassium acetate,
sodium acetate, tripotassium phosphate, sodium butoxide, potassium butoxide,
sodium carbonate,
potassium carbonate, cesium carbonate, sodium bicarbonate, potassium
bicarbonate, calcium
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hydroxide, and triethylamine. In some embodiments, the base is selected from
the group
consisting of sodium acetate, potassium acetate, and tripotassium phosphate.
In some
embodiments, the base is potassium acetate.
[0102] In some embodiments, the polar solvent is selected from the group
consisting of water,
acetic acid, formic acid, methanol, ethanol, n-propanol, t-butanol, DMF, 1,4-
dioxane, and
combinations thereof. In some embodiments, the polar solvent comprises a
combination of at
least two of water, DMF, and 1,4-dioxane. In some embodiments, the polar
solvent comprises a
combination of water and DMF. In some embodiments, the polar solvent comprises
a
combination of DMF and 1,4-dioxane. In some embodiments, the polar solvent
comprises a
combination of water and 1,4-dioxane. In some embodiments, the polar solvent
is 1,4-dioxane. In
some embodiments, the polar solvent is DMF.
[0103] In some embodiments, the coupling reaction is conducted at a
temperature from more
than about 10 C, more than about 20 C, more than about 30 C, more than
about 40 C, more
than about 50 C, more than about 60 C, more than about 70 C, more than
about 80 C, more
than about 90 C, more than about 100 C, more than about 110 C, more than
about 120 C,
more than about 130 C, more than about 140 C, less than about 150 C, less
than about 140 C,
less than about 130 C, less than about 120 C, less than about 110 C, less
than about 100 C,
less than about 90 C, less than about 80 C, less than about 70 C, less than
about 60 C, less
than about 50 C, less than about 40 C, less than about 30 C, less than
about 20 C, from about
C to about 150 C, from about 20 C to about 140 C, from about 30 C to about
130 C,
from about 40 C to about 120 C, from about 50 C to about 110 C, from about
60 C to about
110 C, from about 70 C to about 100 C, from about 70 C to about 90 C,
from about 80 C to
about 90 C, from about 70 C to about 80 C, from about 75 C to about 85 C,
or from about 85
C to about 95 C.
[0104] In some embodiments, the compound of formula (I-D):
0
N/J-,N,R4
(I-D)
is synthesized by treating a compound of formula (I-F)
R5y.
N
N NR
H (I-F)
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with a suitable boron-containing reagent in the presence of a palladium-based
catalyst, a base,
and a polar solvent, wherein R5 is independently selected from a halogen, -0Ts
(where "OTs" is
0(S02)C6H4-4-CH3), and -OMs (where "OMs" is 0(S02)CH3).
[0105] In some embodiments, the boron-containing reagent is a diboron agent.
In some
embodiments, the boron-containing reagent is bis(pinacolato)diboron. In some
embodiments, the
palladium-based catalyst is selected from the group consisting of Pd(PPh3)4,
Pd(OAc)2,
Pd(dppf)C12, Pd(dtbpf)C12, Pd(dba)2, Pd(PCy3)2, Pd(dppe)C12, Pd(t-Bu3P)2,
PdC12[P(o-To1)3]2,
benzylbis(triphenylphosphine)palladium(II) chloride, (A-Phos)2C12Pd, Na2PdC14,
and
PdC12(PPh3)4. In some embodiments, the palladium-based catalyst is selected
from the group
consisting of Pd(PPh3)4, Pd(dppf)C12 and PdC12(PPh3)4. In some embodiments,
the palladium-
based catalyst is Pd(dppf)C12.
[0106] In some embodiments, the base is selected from the group consisting of
lithium
hydroxide, sodium hydroxide, potassium hydroxide, ammonium hydroxide,
potassium acetate,
sodium acetate, tripotassium phosphate, sodium butoxide, potassium butoxide,
sodium carbonate,
potassium carbonate, cesium carbonate, sodium bicarbonate, potassium
bicarbonate, calcium
hydroxide, and triethylamine. In some embodiments, the base is selected from
the group
consisting of sodium acetate, potassium acetate, and tripotassium phosphate.
In some
embodiments, the base is potassium acetate.
[0107] In some embodiments, the polar solvent is selected from the group
consisting of water,
acetic acid, formic acid, methanol, ethanol, n-propanol, t-butanol, and 1,4-
dioxane. In some
embodiments, the polar solvent is 1,4-dioxane.
[0108] In some embodiments, the compound of formula (I-F) is:
Br
and is synthesized from 5-bromopyrazine-2-amine (or 2-amino-5-bromopyrazine).
[0109] In some embodiments, the compound of formula (I-F) is in a form
selected from the
group consisting of a solid, a liquid, and a solution. In some embodiments,
the solid is a
crystalline solid or an amorphous solid. In some embodiments, the solid is a
crystalline solid.
[0110] In some embodiments, the compound of formula (I-B):
0
X
(R3)m (I-B)
is synthesized by treating a compound of formula (I-G):
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0
HO (110
(R3)rn (I-G)
with an acyl halide preparation agent.
[0111] In some embodiments, the acyl halide preparation agent is selected from
the group
consisting of oxalyl chloride, thionyl chloride, phosphoryl chloride,
phosphorus trichloride,
methanesulfonyl chloride, trichloromethanesulfonyl chloride, tert-butyl
hypochlorite,
dichloromethyl methyl ether, methoxyacetyl chloride, cyanuric chloride, N-
chlorosuccinamide,
N-chlorophthalimide, and trimethylsilyl chloride. In some embodiments, the
acyl halide
preparation agent is selected from the group consisting of oxalyl chloride,
thionyl chloride,
phosphoryl chloride, and phosphorus trichloride. In some embodiments, the acyl
halide
preparation agent is oxalyl chloride.
[0112] One aspect described herein is a process of synthesizing CRAC channel
inhibitors. In
some embodiments, the CRAC channel inhibitors are compounds of Formula (1E):
R2
R1?\0
N 0 R3
,
N
R3 (1E),
wherein the process comprises contacting a compound of Formula (IE-A):
R2
N
N
NH2 (1E-A)
with a compound of Formula (IE-B):
0 R3
X
R3 (IE-B)
in the presence of a tertiary amine base and an aprotic polar solvent, wherein
X is -Cl, -Br, -I, -
CN, -N3, -OCH3, -OCH2CH3, -006H5, -006H4-4-NO2, -0C(0)CH3, -0C(0)C6H5, -
0(S02)CH3,
or -0(S02)C6H4-4-CH3.
[0113] In some embodiments, the tertiary amine base is selected from the group
consisting of
pyridine, triethylamine, triisopropyl amine, tributylamine, 2-tert-buty1-
1,1,3,3-
tetramethylguanidine, 4-dimethylaminopyridine, N,N-diisopropylethylamine, 1,8-
diazabicycloundec-7-ene, 1,5-diazabicyclo(4.3.0)non-5-ene, 2,6-di-tert-
butylpyridine, 1,8-
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bis(dimethylamino)naphthalene, 2,6-lutidine, 1,1,3,3-tetramethylguanidine,
2,2,6,6-
tetramethylpiperidine, 2,4,6-trimethylpyridine, 1,4-diazabicyclo(2.2.2)octane,
N,N-
dicyclohexylmethylamine, quinuclidine, pempidine, 1,5,7-
triazabicyclo(4.4.0)dec-5-ene, 7-
methy1-1,5,7-triazabicyclo(4.4.0)dec-5-ene, 3,3,6,9,9-pentamethy1-2,10-
diazabicyclo-(4.4.0)dec-
1-ene, and N-methylmorpholine. In some embodiments, the tertiary amine base is
selected from
the group consisting of pyridine, triethylamine, triisopropyl amine, 2-tent-
buty1-1,1,3,3-
tetramethylguanidine, 4-dimethylaminopyridine, N,N-diisopropylethylamine and N-
methylmorpholine. In some embodiments, the tertiary amine base is pyridine.
[0114] In some embodiments, the aprotic polar solvent is selected from the
group consisting of
chloroform, N-methylpyrrolidone, tetrahydrofuran, ethyl acetate, acetone,
dimethylformamide,
dimethylacetamide, acetonitrile, dimethyl sulfoxide, propylene carbonate,
dichloromethane, and
mixtures thereof. In some embodiments, the aprotic polar solvent is selected
from the group
consisting of chloroform, dichloromethane, and mixtures thereof In some
embodiments, the
aprotic polar solvent is dichloromethane.
[0115] In some embodiments, the compound of Formula (1E-A):
R2
R2 NL
R1\
0
NH2 (rE-A)
is synthesized by treating a compound of formula (LE-C):
R2
Ri 0
R;><0
N
R`, N
(1E-C)
with an acid, wherein R4 is selected from the group consisting of trityl, t-
butyl, t-butoxycarbonyl,
p-tolyl, benzoyl, acetyl and benzyl.
[0116] In some embodiments, the acid is selected from the group consisting of
trifluoroacetic
acid, 2, 2, 2-trifluoroethanol, sulfuric acid, nitric acid, hydrofluoric acid,
hydrobromic acid,
hydroiodic acid, triflic acid, perchloric acid, phosphoric acid, chloric acid,
methanesulfonic acid,
p-toluenesulfonic acid, acetic acid, formic acid, and hydrochloric acid. In
some embodiments, the
acid is selected from the group consisting of trifluoroacetic acid, 2, 2, 2-
trifluoroethanol, sulfuric
acid, and hydrochloric acid. In some embodiments, the acid is hydrochloric.
[0117] In some embodiments, the compound of Formula (1E-A):
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R2
/0
R17\
0 N
1
R` Ni-.
NH2 (rE_A)
is synthesized by subjecting a compound of formula (IE-C):
R2
Ri
0 N
Rµ,
R4
(IE-C)
to a hydrogenation or metal reduction, wherein R4 is selected from the group
consisting of trityl,
t-butyl, p-tolyl, benzoyl, acetyl and benzyl. In some embodiments, R4 is
selected from the group
consisting of trityl, t-butyl, p-tolyl, and benzyl. In some embodiments, R4 is
selected from the
group consisting of trityl and benzyl. In some embodiments, R4 is benzyl. In
some embodiments,
R4 is trityl.
[0118] In some embodiments, the hydrogenation uses a metal catalyst selected
from the group
consisting of Ni, Raney Ni, Pd/C, Degussa type catalyst, Pt/C, and Pd(OAc)2.
In some
embodiments, the hydrogenation uses a metal catalyst selected from the group
consisting of Ni,
Raney Ni, and Pd/C. In some embodiments, the hydrogenation uses a metal
catalyst selected
from the group consisting of Ni or Raney Ni. In some embodiments, the
hydrogenation catalyst is
Ni. In some embodiments, the hydrogenation catalyst is Raney Ni.
[0119] In some embodiments, the metal reduction uses a metal selected from the
group
consisting of lithium, sodium, and potassium, and the metal reduction
optionally uses a catalyst.
In some embodiments the catalyst is naphthalene. In some embodiments, the
metal reduction
uses a metal that is lithium and a catalyst that is naphthalene.
[0120] In some embodiments, the compound of formula (IE-C):
R2
RA
N
Rµ,
R4
(1E-C)
is synthesized by coupling a compound of formula (1E-D):
0
0I N
N NR
(1E-D)
and a compound of formula (IE-E):
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Ri 0 R2
0 Br
R2 (IE-E)
in the presence of a coupling catalyst.
[0121] In some embodiments, the compound of formula (IE-C) is synthesized by
coupling a
compound of formula (IE-D) and a compound of formula (IE-E) in the presence of
a coupling
catalyst, a base, and a polar solvent.
[0122] In some embodiments, the coupling catalyst is a palladium-based
catalyst. In some
embodiments, the palladium-based catalyst is selected from the group
consisting of Pd(PPh3)4,
Pd(OAc)2, Pd(dppf)C12, Pd(dtbpf)C12, Pd(dba)2, Pd(PCy3)2, Pd(dppe)C12, Pd(t-
Bu3P)2, PdC12[P(o-
Top+, benzylbis(triphenylphosphine)palladium(II) chloride, (A-Phos)2C12Pd,
Na2PdC14, SPhos
(2-(2',6"-dimethoxybiphenyl)dicyclohexylphospine),and PdC12(PPh3)4. In some
embodiments,
the palladium-based catalyst is selected from the group consisting of
Pd(PPh3)4, Pd(dppf)C12 and
PdC12(PPh3)4. In some embodiments, the palladium-based catalyst is Pd(PPh3)4.
[0123] In some embodiments, the base is selected from the group consisting of
lithium
hydroxide, sodium hydroxide, potassium hydroxide, ammonium hydroxide,
potassium acetate,
sodium acetate, tripotassium phosphate, sodium butoxide, potassium butoxide,
sodium carbonate,
potassium carbonate, cesium carbonate, sodium bicarbonate, potassium
bicarbonate, calcium
hydroxide, and triethylamine. In some embodiments, the base is selected from
the group
consisting of sodium acetate, potassium acetate, and tripotassium phosphate.
In some
embodiments, the base is potassium acetate.
[0124] In some embodiments, the polar solvent is selected from the group
consisting of water,
acetic acid, formic acid, methanol, ethanol, n-propanol, t-butanol, DMF, 1,4-
dioxane, and
combinations thereof. In some embodiments, the polar solvent comprises a
combination of at
least two of water, DMF, and 1,4-dioxane. hi some embodiments, the polar
solvent comprises a
combination of water and DMF. In some embodiments, the polar solvent comprises
a
combination of DMF and 1,4-dioxane. In some embodiments, the polar solvent
comprises a
combination of water and 1,4-dioxane. In some embodiments, the polar solvent
is 1,4-dioxane. hi
some embodiments, the polar solvent is DMF.
[0125] In some embodiments, the coupling reaction is conducted at a
temperature from more
than about 10 C, more than about 20 C, more than about 30 C, more than
about 40 C, more
than about 50 C, more than about 60 C, more than about 70 C, more than
about 80 C, more
than about 90 C, more than about 100 C, more than about 110 C, more than
about 120 C,
more than about 130 C, more than about 140 C, less than about 150 C, less
than about 140 C,
less than about 130 C, less than about 120 C, less than about 110 C, less
than about 100 C,
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less than about 90 C, less than about 80 C, less than about 70 C, less than
about 60 C, less
than about 50 C, less than about 40 C, less than about 30 C, less than
about 20 C, from about
C to about 150 C, from about 20 C to about 140 C, from about 30 C to about
130 C,
from about 40 C to about 120 C, from about 50 C to about 110 C, from about
60 C to about
110 C, from about 70 C to about 100 C, from about 70 C to about 90 C,
from about 80 C to
about 90 C, from about 70 C to about 80 C, from about 75 C to about 85 C,
or from about 85
C to about 95 C.
[0126] In some embodiments, the compound of formula (IE-D):
0
0I N
N.,c)N,R4
(IE-D)
is synthesized by treating a compound of formula (IE-F)
N
(IE-F)
with a suitable boron-containing reagent in the presence of a palladium-based
catalyst, a base,
and a polar solvent,wherein R5 is independently selected from a halogen, OTs,
and OMs.
[0127] In some embodiments, the boron-containing reagent is a diboron agent.
In some
embodiments, the boron-containing reagent is bis(pinacolato)diboron. In some
embodiments, the
palladium-based catalyst is selected from the group consisting of Pd(PPh3)4,
Pd(OAc)2,
Pd(dppf)C12, Pd(dtbpf)C12, Pd(dba)2, Pd(PCy3)2, Pd(dppe)C12, Pd(t-Bu3P)2,
PdC12[P(o-To1)3[2,
benzylbis(triphenylphosphine)palladium(II) chloride, (A-Phos)2C12Pd, Na2PdC14,
and
PdC12(PPh3)4. In some embodiments, the palladium-based catalyst is selected
from the group
consisting of Pd(PPh3)4, Pd(dppf)C12 and PdC12(PPh3)4. In some embodiments,
the palladium-
based catalyst is Pd(dppf)C12.
[0128] In some embodiments, the base is selected from the group consisting of
lithium
hydroxide, sodium hydroxide, potassium hydroxide, ammonium hydroxide,
potassium acetate,
sodium acetate, tripotassium phosphate, sodium butoxide, potassium butoxide,
sodium carbonate,
potassium carbonate, cesium carbonate, sodium bicarbonate, potassium
bicarbonate, calcium
hydroxide, and triethylamine. In some embodiments, the base is selected from
the group
consisting of sodium acetate, potassium acetate, and tripotassium phosphate.
In some
embodiments, the base is potassium acetate.
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[0129] In some embodiments, the polar solvent is selected from the group
consisting of water,
acetic acid, formic acid, methanol, ethanol, n-propanol, t-butanol, and 1,4-
dioxane. In some
embodiments, the polar solvent is 1,4-dioxane.
[0130] In some embodiments, the compound of formula (TE-F):
Br
Y'
,R4
H 0E-0
is formed by protecting 5-bromopyrazine-2-amine.
[0131] In some embodiments, the compound of formula (IE-F) is in a form
selected from the
group consisting of a solid, a liquid, and a solution. In some embodiments,
the solid is a
crystalline solid or an amorphous solid. In some embodiments, the solid is a
crystalline solid.
[0132] In some embodiments, the compound of formula (IE-B):
0 R3
x 11101
R3 (IE-B)
is synthesized by treating a compound of formula (IE-G):
0 R3
HO
R3 (IE-G)
with an acyl halide preparation agent.
[0133] In some embodiments, the acyl halide preparation agent is selected from
the group
consisting of oxalyl chloride, thionyl chloride, phosphoryl chloride,
phosphorus trichloride,
methanesulfonyl chloride, trichloromethanesulfonyl chloride, tert-butyl
hypochlorite,
dichloromethyl methyl ether, methoxyacetyl chloride, cyanuric chloride, N-
chlorosuccinamide,
N-chlorophthalimide, and trimethylsilyl chloride. In some embodiments, the
acyl halide
preparation agent is selected from the group consisting of oxalyl chloride,
thionyl chloride,
phosphoryl chloride, and phosphorus trichloride. In some embodiments, the acyl
halide
preparation agent is oxalyl chloride.
[0134] One aspect described herein is a process of synthesizing CRAC channel
inhibitors. In
some embodiments, the CRAC channel inhibitors are compounds of Formula (IG);
R2
p
R1?\
I N 0 R3
NN
R3 (IG),
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wherein the process comprises contacting a compound of Formula (IG-A):
R2
N
NH2 (IG-A)
with a compound of Formula (IG-B):
0 R3
X 1101
R3 (IG-B)
in the presence of a tertiary amine base and an aprotic polar solvent, wherein
X is -Cl, -Br, -I, -
CN, -N3, -OCH3, -OCH2CH3, -006H5, -006H4-4-NO2, -0C(0)CH3, -0C(0)C6H5, -
0(S02)CH3,
or -0(802)C6H4-4-CH3.
101351 In some embodiments, the tertiary amine base is selected from the group
consisting of
pyridine, triethylamine, triisopropyl amine, tributylamine, 2-tert-buty1-
1,1,3,3-
tetramethylguanidine, 4-dimethylaminopyridine, NN-diisopropylethylamine, 1,8-
diazabicycloundec-7-ene, 1,5-diazabicyclo(4.3.0)non-5-ene, 2,6-di-tert-
butylpyridine, 1,8-
bis(dimethylamino)naphthalene, 2,6-lutidine, 1,1,3,3-tetramethylguanidine,
2,2,6,6-
tetramethylpiperidine, 2,4,6-trimethylpyridine, 1,4-diazabicyclo(2.2.2)octane,
N,N-
dicyclohexylmethylamine, quinuclidine, pempidine, 1,5,7-
triazabicyclo(4.4.0)dec-5-ene, 7-
methy1-1,5,7-triazabicyclo(4.4.0)dec-5-ene, 3,3,6,9,9-pentamethy1-2,10-
diazabicyclo-(4.4.0)dec-
1-ene, and N-methylmorpholine. In some embodiments, the tertiary amine base is
selected from
the group consisting of pyridine, triethylamine, triisopropyl amine, 2-tert-
buty1-1,1,3,3-
tetramethylguanidine, 4-dimethylaminopyridine, N, N-diisopropylethylamine and
N-
methylmorpholine. In some embodiments, the tertiary amine base is pyridine.
101361 In some embodiments, the aprotic polar solvent is selected from the
group consisting of
chloroform, N-methylpyrrolidone, tetrahydrofuran, ethyl acetate, acetone,
dimethylformamide,
dimethylacetamide, acetonitrile, dimethyl sulfoxide, propylene carbonate,
dichloromethane, and
mixtures thereof. In some embodiments, the aprotic polar solvent is selected
from the group
consisting of chloroform, dichloromethane, and mixtures thereof. In some
embodiments, the
aprotic polar solvent is dichloromethane.
101371 In some embodiments, the compound of Formula (IG-A):
R2
Ri
NH2 (IG-A)
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is synthesized by treating a compound of formula (IG-C):
R2
R1\
0 N
(IG-C)
with an acid, wherein R4 is selected from the group consisting of trityl, t-
butyl, t-butoxycarbonyl,
p-tolyl, benzoyl, acetyl and benzyl.
[0138] In some embodiments, the acid is selected from the group consisting of
trifluoroacetic
acid, 2, 2, 2-trifluoroethanol, sulfuric acid, nitric acid, hydrofluoric acid,
hydrobromic acid,
hydroiodic acid, triflic acid, perchloric acid, phosphoric acid, chloric acid,
methanesulfonic acid,
p-toluenesulfonic acid, acetic acid, formic acid, and hydrochloric acid. In
some embodiments, the
acid is selected from the group consisting of trifluoroacetic acid, 2, 2, 2-
trifluoroethanol, sulfuric
acid, and hydrochloric acid. In some embodiments, the acid is hydrochloric.
[0139] In some embodiments, the compound of Formula (IG-A):
R2
Ri
R1'\
0 N
NH2 (IG-A)
is synthesized by subjecting a compound of formula (IG-C):
R2
R JO
R1\
0 N
(IG-C)
to a hydrogenation or metal reduction, wherein R4 is selected from the group
consisting of trityl,
t-butyl, p-tolyl, benzoyl, acetyl and benzyl. In some embodiments, R4 is
selected from the group
consisting of trityl, t-butyl, p-tolyl, and benzyl. In some embodiments, R4 is
selected from the
group consisting of trityl and benzyl. In some embodiments, R4 is benzyl. In
some embodiments,
R4 is trityl.
[0140] In some embodiments, the hydrogenation uses a metal catalyst selected
from the group
consisting of Ni, Raney Ni, Pd/C, Degussa type catalyst, Pt/C, and Pd(OAc)2.
In some
embodiments, the hydrogenation uses a metal catalyst selected from the group
consisting of Ni,
Raney Ni, and Pd/C. In some embodiments, the hydrogenation uses a metal
catalyst selected
from the group consisting of Ni or Raney Ni. In some embodiments, the
hydrogenation catalyst is
Ni. In some embodiments, the hydrogenation catalyst is Raney Ni.
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[0141] In some embodiments, the metal reduction uses a metal selected from the
group
consisting of lithium, sodium, and potassium, and the metal reduction
optionally uses a catalyst.
In some embodiments the catalyst is naphthalene. In some embodiments, the
metal reduction
uses a metal that is lithium and a catalyst that is naphthalene.
[0142] In some embodiments, the compound of formula (IG-C):
R2
Ri
0
I N
N , R4
(IG-C)
is synthesized by coupling a compound of formula (IG-D):
0
0
B
N
I I
N N R4
(IG-D)
and a compound of formula (IG-E):
R2
R 1/3
Br (IG-E)
in the presence of a coupling catalyst.
[0143] In some embodiments, the compound of formula (IG-C) is synthesized by
coupling a
compound of formula (IG-D) and a compound of formula (IG-E) in the presence of
a coupling
catalyst, a base, and a polar solvent.
[0144] In some embodiments, the coupling catalyst is a palladium-based
catalyst. In some
embodiments, the palladium-based catalyst is selected from the group
consisting of Pd(PPh3)4,
Pd(OAc)2, Pd(dppf)C12, Pd(dtbpf)C12, Pd(dba)2, Pd(PCy3)2, Pd(dppe)C12, Pd(t-
Bu3P)2, PdC12[P(o-
Top+, benzylbis(triphenylphosphine)palladium(II) chloride, (A-Phos)2C12Pd,
Na2PdC14, SPhos
(2-(2',6"-dimethoxybiphenyl)dicyclohexylphospine),and PdC12(PPh3)4. In some
embodiments,
the palladium-based catalyst is selected from the group consisting of
Pd(PPh3)4, Pd(dppf)C12 and
PdC12(PPh3)4. In some embodiments, the palladium-based catalyst is Pd(PPh3)4.
[0145] In some embodiments, the base is selected from the group consisting of
lithium
hydroxide, sodium hydroxide, potassium hydroxide, ammonium hydroxide,
potassium acetate,
sodium acetate, tripotassium phosphate, sodium butoxide, potassium butoxide,
sodium carbonate,
potassium carbonate, cesium carbonate, sodium bicarbonate, potassium
bicarbonate, calcium
hydroxide, and triethylamine. In some embodiments, the base is selected from
the group
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consisting of sodium acetate, potassium acetate, and tripotassium phosphate.
In some
embodiments, the base is potassium acetate.
[0146] In some embodiments, the polar solvent is selected from the group
consisting of water,
acetic acid, formic acid, methanol, ethanol, n-propanol, t-butanol, DMF, 1,4-
dioxane, and
combinations thereof. In some embodiments, the polar solvent comprises a
combination of at
least two of water, DMF, and 1,4-dioxane. In some embodiments, the polar
solvent comprises a
combination of water and DIVff. In some embodiments, the polar solvent
comprises a
combination of DMF and 1,4-dioxane. In some embodiments, the polar solvent
comprises a
combination of water and 1,4-dioxane. In some embodiments, the polar solvent
is 1,4-dioxane. In
some embodiments, the polar solvent is DMF.
[0147] In some embodiments, the coupling reaction is conducted at a
temperature from more
than about 10 C, more than about 20 C, more than about 30 C, more than
about 40 C, more
than about 50 C, more than about 60 C, more than about 70 C, more than
about 80 C, more
than about 90 C, more than about 100 C, more than about 110 C, more than
about 120 C,
more than about 130 C, more than about 140 C, less than about 150 C, less
than about 140 C,
less than about 130 C, less than about 120 C, less than about 110 C, less
than about 100 C,
less than about 90 C, less than about 80 C, less than about 70 C, less than
about 60 C, less
than about 50 C, less than about 40 C, less than about 30 C, less than
about 20 C, from about
C to about 150 C, from about 20 C to about 140 C, from about 30 C to about
130 C,
from about 40 C to about 120 C, from about 50 C to about 110 C, from about
60 C to about
110 C, from about 70 C to about 100 C, from about 70 C to about 90 C,
from about 80 C to
about 90 C, from about 70 C to about 80 C, from about 75 C to about 85 C,
or from about 85
C to about 95 C.
[0148] In some embodiments, the compound of formula (IG-D):
0
0I N
(IG-D)
is synthesized by treating a compound of formula (IG-F)
N
N /1,N,R4
H (IG-F)
with a suitable boron-containing reagent in the presence of a palladium-based
catalyst, a base,
and a polar solvent,wherein R5 is independently selected from a halogen, OTs,
and OMs.
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[0149] In some embodiments, the boron-containing reagent is a diboron agent.
In some
embodiments, the boron-containing reagent is bis(pinacolato)diboron. In some
embodiments, the
palladium-based catalyst is selected from the group consisting of Pd(PPh3)4,
Pd(OAc)2,
Pd(dppf)C12, Pd(dtbpf)C12, Pd(dba)2, Pd(PCy3)2, Pd(dppe)C12, Pd(t-Bu3P)2,
PdC12[P(o-To1)3]2,
benzylbis(triphenylphosphine)palladium(II) chloride, (A-Phos)2C12Pd, Na2PdC14,
and
PdC12(PPh3)4. In some embodiments, the palladium-based catalyst is selected
from the group
consisting of Pd(PPh3)4, Pd(dppf)C12 and PdC12(PPh3)4. In some embodiments,
the palladium-
based catalyst is Pd(dppf)C12.
[0150] In some embodiments, the base is selected from the group consisting of
lithium
hydroxide, sodium hydroxide, potassium hydroxide, ammonium hydroxide,
potassium acetate,
sodium acetate, tripotassium phosphate, sodium butoxide, potassium butoxide,
sodium carbonate,
potassium carbonate, cesium carbonate, sodium bicarbonate, potassium
bicarbonate, calcium
hydroxide, and triethylamine. In some embodiments, the base is selected from
the group
consisting of sodium acetate, potassium acetate, and tripotassium phosphate.
In some
embodiments, the base is potassium acetate.
[0151] In some embodiments, the polar solvent is selected from the group
consisting of water,
acetic acid, formic acid, methanol, ethanol, n-propanol, t-butanol, and 1,4-
dioxane. In some
embodiments, the polar solvent is 1,4-dioxane.
[0152] In some embodiments, the compound of formula (IG-F):
NR4
H (IG-F)
is formed by protecting 5-bromopyrazine-2-amine.
[0153] In some embodiments, the compound of formula (IG-F) is in a form
selected from the
group consisting of a solid, a liquid, and a solution. In some embodiments,
the solid is a
crystalline solid or an amorphous solid. In some embodiments, the solid is a
crystalline solid.
[0154] In some embodiments, the compound of formula (IG-B):
0 R3
x
R3 (IG-B)
is synthesized by treating a compound of formula (IG-G):
0 R3
HO
R3 (IG-G)
with an acyl halide preparation agent.
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[0155] In some embodiments, the acyl halide preparation agent is selected from
the group
consisting of oxalyl chloride, thionyl chloride, phosphoryl chloride,
phosphorus trichloride,
methanesulfonyl chloride, trichloromethanesulfonyl chloride, tert-butyl
hypochlorite,
dichloromethyl methyl ether, methoxyacetyl chloride, cyanuric chloride, N-
chlorosuccinamide,
N-chlorophthalimide, and trimethylsilyl chloride. In some embodiments, the
acyl halide
preparation agent is selected from the group consisting of oxalyl chloride,
thionyl chloride,
phosphoryl chloride, and phosphorus trichloride. In some embodiments, the acyl
halide
preparation agent is oxalyl chloride.
[0156] One aspect described herein is a process of synthesizing a CRAC channel
inhibitor,
wherein the CRAC channel inhibitor is a compound of Formula (II):
Fo./0 CI
F0 .'1\1 0 CH3
401
(II) and,
wherein the process comprises contacting a compound of Formula (II-A):
Fx0 CI
F N
N
NH2 (II-A)
with a compound of Formula (II-B):
0 cH3
CI
(II-B)
in the presence of a tertiary amine base and an aprotic polar solvent.
[0157] In some embodiments, the tertiary amine base is selected from the group
consisting of
pyridine, triethylamine, triisopropyl amine, tributylamine, 2-tert-buty1-
1,1,3,3-
tetramethylguanidine, 4-dimethylaminopyridine, N,N-diisopropylethylamine, 1,8-
diazabicycloundec-7-ene, 1,5-diazabicyclo(4.3.0)non-5-ene, 2,6-di-tert-
butylpyridine, 1,8-
bis(dimethylamino)naphthalene, 2,6-lutidine, 1,1,3,3-tetramethylguanidine,
2,2,6,6-
tetramethylpiperidine, 2,4,6-trimethylpyridine, 1,4-diazabicyclo(2.2.2)octane,
N,N-
dicyclohexylmethylamine, quinuclidine, pempidine, 1,5,7-
triazabicyclo(4.4.0)dec-5-ene, 7-
methy1-1,5,7-triazabicyclo(4.4.0)dec-5-ene, 3,3,6,9,9-pentamethy1-2,10-
diazabicyclo-(4.4.0)dec-
1-ene, and N-methylmorpholine. In some embodiments, the tertiary amine base is
selected from
the group consisting of pyridine, triethylamine, triisopropyl amine, 2-tert-
buty1-1,1,3,3-
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tetramethylguanidine, 4-dimethylaminopyridine, N, N-diisopropylethylamine and
N-
methylmorpholine. In some embodiments, the tertiary amine base is pyridine.
[0158] In some embodiments, the aprotic polar solvent is selected from the
group consisting of
chloroform, N-methylpyrrolidone, tetrahydrofuran, ethyl acetate, acetone,
dimethylformamide,
dimethylacetamide, acetonitrile, dimethyl sulfoxide, propylene carbonate,
dichloromethane, and
mixtures thereof. In some embodiments, the aprotic polar solvent is selected
from the group
consisting of chloroform, dichloromethane, and mixtures thereof In some
embodiments, the
aprotic polar solvent is dichloromethane.
[0159] In some embodiments, wherein the compound of Formula (II-A):
F,x0 CI
F 0 N
N H2 (ILA)
is synthesized by treating a compound of formula (IT-C)
F \c)
..1\1 Ph
)Ph
N ph
with an acid.
[0160] In some embodiments, the acid is selected from the group consisting of
trifluoroacetic
acid, 2, 2, 2-trifluoroethanol, sulfuric acid, nitric acid, hydrofluoric acid,
hydrobromic acid,
hydroiodic acid, triflic acid, perchloric acid, phosphoric acid, chloric acid,
methanesulfonic acid,
p-toluenesulfonic acid, acetic acid, formic acid, and hydrochloric acid. In
some embodiments, the
acid is selected from the group consisting of trifluoroacetic acid, 2, 2, 2-
trifluoroethanol, sulfuric
acid, and hydrochloric acid. In some embodiments, the acid is hydrochloric
acid.
[0161] In some embodiments, the compound of Formula (II-A):
Fx0 CI
F N
NH2 (II-A)
is synthesized by subjecting a compound of formula (IT-C):
F/0 CI
\c)
N Ph
N A-Ph
N ph
(II-C)
to a hydrogenation or metal reduction.
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[0162] In some embodiments, the hydrogenation uses a metal catalyst selected
from the group
consisting of Ni, Raney Ni, Pd/C, Degussa type catalyst, Pt/C, and Pd(OAc)2.
In some
embodiments, the hydrogenation uses a metal catalyst selected from the group
consisting of Ni,
Raney Ni, and Pd/C. In some embodiments, the hydrogenation uses a metal
catalyst selected
from the group consisting of Ni or Raney Ni. In some embodiments, the
hydrogenation catalyst is
Ni. In some embodiments, the hydrogenation catalyst is Raney Ni.
[0163] In some embodiments, the metal reduction uses a metal selected from the
group
consisting of lithium, sodium, and potassium, and the metal reduction
optionally uses a catalyst.
In some embodiments the catalyst is naphthalene. In some embodiments, the
metal reduction
uses a metal that is lithium and a catalyst that is naphthalene.
[0164] In some embodiments, the compound of formula (IT-C):
0 CI
r
0 .1\1 Ph
N . A-Ph
N ph
is synthesized by coupling a compound of formula (II-D):
0
0IN Ph
ph
(II-D)
and a compound of formula (II-E):
N/0 410 CI
E--"N
' 0 Br (II-E)
in the presence of a coupling catalyst.
[0165] In some embodiments, the compound of formulat (TI-C) is synthesized by
coupling a
compound of formula (II -D) and a compound of formula (II-E) in the presence
of a coupling
catalyst, a base, and a polar solvent.
[0166] In some embodiments, the coupling catalyst is a palladium-based
catalyst. In some
embodiments, the palladium-based catalyst is selected from the group
consisting of Pd(PPh3)4,
Pd(OAc)2, Pd(dppf)C12, Pd(dtbpf)C12, Pd(dba)2, Pd(PCy3)2, Pd(dppe)C12, Pd(t-
Bu3P)2,
PdC12[P(o-To1)3]2, benzylbis(triphenylphosphine)palladium(II) chloride, (A-
Phos)2C12Pd,
Na2PdC14, SPhos (2-(2',6"-dimethoxybiphenyl)dicyclohexylphospine), and
PdC12(PPh3)4. In
some embodiments, the palladium-based catalyst is selected from the group
consisting of
Pd(PPh3)4, Pd(dppf)C12 and PdC12(PPh3)4. In some embodiments, the palladium-
based catalyst is
Pd(PPh3)4.
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[0167] In some embodiments, the base is selected from the group consisting of
lithium
hydroxide, sodium hydroxide, potassium hydroxide, ammonium hydroxide,
potassium acetate,
sodium acetate, tripotassium phosphate, sodium butoxide, potassium butoxide,
sodium carbonate,
potassium carbonate, cesium carbonate, sodium bicarbonate, potassium
bicarbonate, calcium
hydroxide, and triethylamine. In some embodiments, the base is selected from
the group
consisting of sodium acetate, potassium acetate, and tripotassium phosphate.
In some
embodiments, the base is potassium acetate. In some embodiments, the basie is
tripotassium
phosphate. In some embodiments, the base is cesium fluoride.
[0168] In some embodiments, the polar solvent is selected from the group
consisting of water,
acetic acid, formic acid, methanol, ethanol, n-propanol, t-butanol, DMF, 1,4-
dioxane, and
combinations thereof. In some embodiments, the polar solvent comprises a
combination of at
least two of water, DMF, and 1,4-dioxane. In some embodiments, the polar
solvent comprises a
combination of water and DMF. In some embodiments, the polar solvent comprises
a
combination of DMF and 1,4-dioxane. In some embodiments, the polar solvent
comprises a
combination of water and 1,4-dioxane. In some embodiments, the polar solvent
is 1,4-dioxane. In
some embodiments, the polar solvent is DMF.
[0169] In some embodiments, the coupling reaction is conducted at a
temperature from more
than about 10 C, more than about 20 C, more than about 30 C, more than
about 40 C, more
than about 50 C, more than about 60 C, more than about 70 C, more than
about 80 C, more
than about 90 C, more than about 100 C, more than about 110 C, more than
about 120 C,
more than about 130 C, more than about 140 C, less than about 150 C, less
than about 140 C,
less than about 130 C, less than about 120 C, less than about 110 C, less
than about 100 C,
less than about 90 C, less than about 80 C, less than about 70 C, less than
about 60 C, less
than about 50 C, less than about 40 C, less than about 30 C, less than
about 20 C, from about
C to about 150 C, from about 20 C to about 140 C, from about 30 C to about
130 C,
from about 40 C to about 120 C, from about 50 C to about 110 C, from about
60 C to about
110 C, from about 70 C to about 100 C, from about 70 C to about 90 C,
from about 80 C to
about 90 C, from about 70 C to about 80 C, from about 75 C to about 85 C,
or from about 85
C to about 95 C.
[0170] In some embodiments, the compound of formula (II-D):
0
0 'r=-=IN Ph
)<Ph
.N Ph
(II-D)
is synthesized by treating a compound of formula (II-F)
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Bry-,1\1 Ph
)<Ph
N Ph
(II-F)
with bis(pinacolato)diboron in the presence of a palladium-based catalyst, a
base, and a polar
solvent.
[0171] In some embodiments, the palladium-based catalyst is selected from the
group consisting
of Pd(PPh3)4, Pd(OAc)2, Pd(dppf)C12, Pd(dtbpf)C12, Pd(dba)2, Pd(PCy3)2,
Pd(dppe)C12, Pd(t-
Bu3P)2, PdC12[P(o-To1)3]2, benzylbis(triphenylphosphine)palladium(II)
chloride, (A-Phos)2C12Pd,
Na2PdC14, and PdC12(PPh3)4. In some embodiments, the palladium-based catalyst
is selected from
the group consisting of Pd(PPh3)4, Pd(dppf)C12 and PdC12(PPh3)4. In some
embodiments, the
palladium-based catalyst is Pd(dppf)C12.
[0172] In some embodiments, the base is selected from the group consisting of
lithium
hydroxide, sodium hydroxide, potassium hydroxide, ammonium hydroxide,
potassium acetate,
sodium acetate, tripotassium phosphate, sodium butoxide, potassium butoxide,
sodium carbonate,
potassium carbonate, cesium carbonate, sodium bicarbonate, potassium
bicarbonate, calcium
hydroxide, and triethylamine. In some embodiments, the base is selected from
the group
consisting of sodium acetate, potassium acetate, and tripotassium phosphate.
In some
embodiments, the base is potassium acetate.
[0173] In some embodiments, the polar solvent is selected from the group
consisting of water,
acetic acid, formic acid, methanol, ethanol, n-propanol, t-butanol, and 1,4-
dioxane. In some
embodiments, the polar solvent is 1,4-dioxane.
[0174] In some embodiments, the compound of formula (II-F):
Br N Ph
ph
Ph
(II-F)
is synthesized from 2-amino-5-bromopyrazine.
[0175] In some embodiments, the compound of formula (II-F) is synthesized from
2-amino-
5-bromopyrazine by treating 2-amino-5-bromopyrazine with
triphenylmethylchloride in the
presence of a tertiary amine base. In some embodiments, the compound of
formula (II-F) is
synthesized from 2-amino-5-bromopyrazine by treating 2-amino-5-bromopyrazine
with
triphenylmethylchloride in the presence of a tertiary amine base in an aprotic
polar solvent. In
some embodiments, the aprotic polar solvent is dichloromethane. In some
embodiments the
tertiary amine base is triethylamine or pyridine. In some embodiments, the
tertiary amine base is
triethylamine. In some embodiments, the tertiary amine basis is pyridine. In
some embodiments
the tertiary amine base is triethylamine and the aprotic polar solvent is
dichloromethane.
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[0176] In some embodiments, the compound of formula (II-F) is in a form
selected from the
group consisting of a solid, a liquid, and a solution. In some embodiments,
the solid is a
crystalline solid or an amorphous solid. In some embodiments, the solid is a
crystalline solid.
[0177] In some embodiments, the compound of formula (II-B):
0 CH3
CI
(II-B)
is synthesized by treating a compound of formula (II-G):
0 cH3
HO 110
(II-G)
with an acyl halide preparation agent.
[0178] In some embodiments, the acyl halide preparation agent is selected from
the group
consisting of oxalyl chloride, thionyl chloride, phosphoryl chloride,
phosphorus trichloride,
methanesulfonyl chloride, trichloromethanesulfonyl chloride, tert-butyl
hypochlorite,
dichloromethyl methyl ether, methoxyacetyl chloride, cyanuric chloride, N-
chlorosuccinamide,
N-chlorophthalimide, and trimethylsilyl chloride. In some embodiments, the
acyl halide
preparation agent is selected from the group consisting of oxalyl chloride,
thionyl chloride,
phosphoryl chloride, and phosphorus trichloride. In some embodiments, the acyl
halide
preparation agent is oxalyl chloride.
EXAMPLES
[0179] The examples provided herein are for illustrative purposes only and
shall not limit the
scope of the appended claims. The starting materials and reagents used for the
synthesis of the
compounds described herein were synthesized or were obtained from commercial
sources, such
as, but not limited to, Sigma-Aldrich, Acros Organics, Fluka, and Fischer
Scientific. The identity,
yield, and purity of the products of the larger-scale preparations described
herein were verified
and determined using standardized analytical methods developed on the basis of
reference
standards prepared by independent synthesis. In the Examples below, the
nomenclature "n-mX",
where "n-m" recites a range of integers, denotes the approximate factor by
which a given solute
was concentrated by removing excess solvent by selective solvent stripping
(solvent
vaporization). For example, "the solution was concentrated to 4-5X" means
sufficient solvent
was removed to increase the concentration of non-volatile solute(s) to from 4
to 5 times the
original concentration; if the original concentration was 0.2M, "concentrated
to 4-5X" results in a
solution where the solute concentrations has increased to from about 0.8M to
about 1.0M.
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Example 1¨ PREPARATION OF COMPOUND 1.3
Br
Br H N Ph
yl kPh Pd(dppf)C12
1\1N Ph 0-Brrk'N Ph
1\1 )<Ph
DCM KOAc, Dioxane
2Trita, Et3N N Ph
N
bis(pinacolato)diborane)
1.1 1.2 1.3
Preparation of 5-bromo-N-tritylpyrazin-2-amine (1.2):
[0180] 5-bromopyrazin-2-amine (1.1) (3.9 kg, 22.41 moles) was added to DCM (23-
24 L). At
room temperature, the solution was stirred and 3.6 kg triethylamine (Et3N)
(35.57 mol) was
added via head tank. The reaction mixture was cooled to 0-10 C, and a solution
of
triphenylmethyl chloride (7.0 g, 25.11 mol) in DCM (11-13 L) in HIDPE drum was
slowly added
via head tank, not exceeding 0-20 C. The reaction proceeded at 15-20 C for 5-9
hr. Upon
completion, the reaction was quenched with water (-4 L), and was allowed to
stir at 10-25 C for
40-60 min. The layers were separated, and 5% NaCl(ao (-4 L) was added to the
organic layer.
The mixture was stirred for 40-60 mins, and the layers were separated. The
solution was
concentrated to 4-5X, methyl tertiary-butyl ether (MTBE) (15-20 kg) was added,
and the solution
was re-concentrated to 4-5X. This process was repeated 3 times. After the
third iteration of this
process, the subsequent mixture was stirred at 10-20 C for 10-20 min. The
resulting solid was
filtered to produce a wet cake. The cake was dried at 40-50 C for 16-20 hr.
Yield = 8.33 kg.
purity = 96.8%.
Preparation of 5-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-y1)-N-tritylpyrazin-
2-amine
(1.3):
[0181] 1,4-dioxane (28-30 L) was added to 5-bromo-N-tritylpyrazin-2-amine
(1.2) (6.8 kg, 16.33
moles), bis(pinacolato)diboron (4.95 kg, 19.5 moles), and potassium acetate
(KOAc) (2.4 kg). At
room temperature, the solution purged with nitrogen 3 times. Pd(dppf)C12 (1.17
kg, 1.66 moles)
was added, and the solution was purged with nitrogen 3 times. The reaction
proceeded at 80-
90 C for 16-20 hr. Upon completion, the reaction was cooled to 20-30 C, and
the solution was
filtered and concentrated to 2X-4X. The solution was immediately taken to the
next step without
further purification.
Example 2¨ PREPARATION OF COMPOUND 2.3
1.3
o F-x
CI CI CI 1101 NBS, TEA, H2SO4 F(C31
Pd(PPh3)4 F,(c) 101
0 MeCN 0110 Br K3PO4, DMF 0
N Ph
NLA )<Ph
2.1 2.2 N Ph
2.3
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Preparation of 5-bromo-6-chloro-2,2-difluorobenzo[d]11,31dioxole (2.2):
[0182] 5-chloro-2,2-difluorobenzo[d][1,3]dioxole (2.1) (3.0 kg, 15.58 moles)
was added to
MeCN (-2.6 L). At 10-20 C, N-bromosuccinamide (NBS) (2.8-3.2 kg, 17-19 moles)
was added
to the solution. ¨6.5 kg trifluoroacetic acid (TFA) was added slowly at 10-20
C, followed by the
slow addition of ¨6.7 kg sulfuric acid (H2SO4) at 10-20 C. The reaction
proceeded at 15-20 C
for 24-36 hr. A second batch of NBS (-0.35 kg) was added, and the reaction
proceeded at 15-
20 C for 24-36 hr. A third batch of NBS (-0.35 kg) was added, and the reaction
proceeded at 15-
20 C for 24-36 hr. A fourth batch of NBS (-0.35 kg) was added, and the
reaction proceeded at
15-20 C for 24-36 hr. Upon near completion, water (-5.8 L) was added, and the
solution was
cooled to 0-5 C. Methyl tertiary-butyl ether (MTBE) (-5 kg) was added, and the
product was
extracted with MTBE 3 times. Keeping the internal temperature at 0-15 C, the
organic layer was
basified with 10% Na0H(ao (-5 kg) to pH ¨ 10-12. The subsequent mixture was
stirred at 0-
15 C for 40-60 min. They layers were separated, and the subsequent organic
layer was washed
with water (-4 L). Keeping the temperature less than 30 C, the organic layer
was concentrated to
2X-6X under reduced pressure. Yield = 3.54Kg. purity = 87.8%.
Preparation of 5-(6-chloro-2,2-difluorobenzo[d]11,31dioxo1-5-y1)-N-
trity1pyrazin-2-amine
(2.3):
[0183] DMF (-20 L) was added to freshly prepared 5-(4,4,5,5-tetramethy1-1,3,2-
dioxaborolan-2-
y1)-N-tritylpyrazin-2-amine (1.3), and the solution was stirred for 15-30 min.
This solution was
added to previously prepared 5-bromo-6-chloro-2,2-difluorobenzo[d][1,3]dioxole
(2.2) MTBE
solution (2.28 kg, 12.44 moles, net quantity as 1.0X). CsF (-4 kg) and water (-
0.017 kg) were
added, and the solution was degassed 3x with nitrogen. Pd(PPh3)4 (0.94 kg,
0.81 moles) was
added under nitrogen, degassed 3x with nitrogen, and the reaction proceeded at
80-90 C for 1-2
hr. Upon completion, the reaction was cooled to 15-25 C, and water (-4 L) was
added. DCM 0
was added, the mixture was stirred for 30-60 min at 15-25 C, and then the
layers were allowed to
separate. The organic layer was collected, and the reaction container was
cleaned with water and
backwashed with DCM 3x. The organic layers were combined and concentrated to
13X-14X.
Me0H was added and evaporated three times, producing a solid that was
centrifuged. The
mother liquor was removed, and the resulting solid was dissolved in DCM (13X-
14X). The
process of adding and evaporating Me0H was repeated 3 more times, and the
mixture was
centrifuged. The mother liquor was separated, and the resulting solid was
dried at 40-50 C for 5-
hr. The solid was dissolved in DCM, stirring for 30-60 mins at 15-25 C until
clear, and the
solution was filtered through silica gel (5X-8X) twice The resulitng mother
liquor was
concentrated to 13X-14X, and dissolved with MelH (10X-11X), stirring for 30-60
min at 10-
C. The mixture was cetrifuged, and the mother liquor was separated. This
centrifugation
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process was repeated, and the resulting solid was dried at 40-50 C for 16-20
hr. Yield = 3.64 kg.
purity = 99%.
Example 3¨ PREPARATION OF COMPOUND 3.2
0 CH3 0 CH3
HO (1101 (0001)2 CI 401
DMF (cat), DCM
3.1 3.2
Preparation of 2-fluoro-6-methylbenzoyl chloride (3.2):
[0184] DCM (2.5X-3.0X) and DMF (0.00019X-0.00020X) were added to 2-fluoro-6-
methylbenzoic acid (3.1) (0.88 kg, 5.71 moles). At 20-25 C, oxalyl chloride
((C0C1)2) (0.98 kg,
7.72 moles) was added to the solution. The reaction proceeded at 20-30 C for
16-20 hr. A second
batch of DMF (0.00019X-0.00020) was added, and the reaction proceeded at 20-30
C for 10-12
hr. Toluene (5X-6X kg) was added, and the reaction was concentrated to 2-3X,
keeping the
internal temperature less than 40 C. This step was repeated, and maintained
for immediate use.
Example 4¨ PREPARATION OF COMPOUND 4.2
0 CI 4N HCl/Et0H 0 CI 3.2
0 N Ph
Fe- \
0 N pyridine, DCM*-
N Ph
N Ph N./2.N H2
2.3 4.1
F/0 CI
F\
0 N 0 CH3
Ori
4.2
[0185] Preparation of 5-(6-chloro-2,2-difluorobenzo[d][1,31dioxol-5-yl)pyrazin-
2-amine
(4.1):
[0186] Ethyl alcohol (8.5X-9.5X) was added to 5-(6-chloro-2,2-
difluorobenzo[d][1,3]dioxo1-5-
y1)-N-tritylpyrazin-2-amine (2.3) (3.5 kg, 6.56 moles). At 10-20 C, a solution
of 4N HC1 in ethyl
alcohol (3.0X-3.3X) was added dropwise via head tank at 10-20 C The reaction
proceeded at
10-20 C for 2-4 hr. The reaction was filtered via Buchner funnel, and the
mother liquor was
collected and centrifuged. The mother liquor was removed, and the subsequent
crude solid was
dissolved in 2-MeTHY (5.0X-5.5X), stirring for 15-30 min at 10-20 C. 4% NaHCO3
(ac) (5.0X
5.5X) was added dropwise at 10-20 C via head tank until the solution reached
pH 8-9. The
mixture was stirred for 20-40 min at 10-20 C, and then rested for 15-30 min.
The organic layer
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was collected, and a backwash of the aqueous with 2-MeTHF was performed twice.
The organic
layers were combined, and 2-mercaptobenzoic acid (0.09X-1.2X) was added. The
mixture was
stirred at 10-20 C for 1-2 hr. At 10-20 C, 5% Na2CO3 (aq) (3.9X-4.1X) was
added, stirred for 15-
30 mins, and rested for 15-30 mins. The organic layer was collected, and the
Na2CO3 wash was
repeated 3 more times. This was followed by three additional washes with brine
(4.9X-5.1X).
The organic layer was collected, and n-heptane (5.0X-6.5X) was added dropwise
via headtank at
10-20 C. The solution was cooled to 0-5 C and stirred for 2-3 hr. The
resulting solid was filtered,
and the product was dried at 40-50 C for 16-20 hr. Yield = 1.68Kg. purity =
99.2%.
[0187] Preparation of N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxo1-5-
y1)pyrazin-2-y1)-2-
fluoro-6-methylbenzamide (4.2):
[0188] 5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxo1-5-yl)pyrazin-2-amine (4.1)
(1.09 kg, 3.82
moles) and DCM (13.5X-14.5X) were added to freshly prepared 2-fluoro-6-
methylbenzoyl
chloride (3.2). Under nitrogen atmosphere, the reaction was cooled to 0-5 C,
and pyridine (0.98
kg, 12.4 moles) was slowly added via head tank below 5 C. The reaction
proceeded at 0-5 C for
16-20 hr. The addition of pyridine (0.98 kg, 12.4 moles) was performed until
the reaction
completed. Upon completion, 5% NaHCO3 (aq) (10X-10.5X) was added dropwise via
head tank,
keeping the temperature below 20 C. The mixture was stirred at 10-20 C for 1-2
h, and then
allowed to rest for 15-30 min. The bottom layer was collected, and DCM (6.5X-
7.0X) was added.
The solution was stirred for 15-30 min at 10-20 C, and then allowed to rest
for 15-30 mins. The
organic layer was collected and concentrated to 5-6X, keeping the inner
temperature below 40 C.
Three times, THF (10X-11X) was added and concentrated to 5-6X, keeping the
inner
temperature less than 40 C. Me0H (4X-5X) was added at 10-20 C, and 2M NaOH(aq)
(6X-7X)
was added at 20-30 C. The reaction was stirred for 3-6 hr at 30-40 C, or until
completion. The
reaction was cooled to 5-10 C, 6M HC1 (2-5X) was added dropwise via headtank
at 20 C,
adjusting to pH = 9-10. The solution was concentrated to 15X-16X, keeping the
inner
temperature below 40 C. Water (5X-6X) and ethyl acetate (10X-10.5X) were
added; the mixture
was stirred for 15-30 min at 30-40 C, and then allowed to rest for 15-30 min
at 30-40 C. The
organic layer was collected, and this process was repeated. The organic layers
were combined
and washed with water (10X-10.5X) three times. The organic layer was
concentrated to 5X-6X,
keeping the inner temperature below 40 C. n-heptane (10X-105X) was added, the
solution was
cooled to 10-15 C, and the material was filtered and washed with n-helptane
(1X-2X). The
subsequent solid was dissolved in Me0H (19X-21X) at 40-50 C, stirring for 1-2
hr. The solution
was cooled to 20-25 C, and the resulting solid was filtered and rinsed with
Me0H (1-2X) The
resulting solid was mixed with 0.1X silicathiol, stirred for 1-2 hr at 20-30
C, filtered, and rinsed
with Me0H (1X-2X). Concentrate to 5-6X, keeping an inner temperature below 50
C, and then
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add isopropyl alcohol (10X-10.5X). Concentrate to 5-6X, keeping an inner
temperature below
50 C, and then heat to 80-90 C. The solution was stirred for 1-2 hr at 80-90
C, and then cooled
to -10-0 C. The mixture was stirred for 1-2 hr at -10-0 C, and the resulting
solid was filtered and
rinsed with cold isopropanol (1X-2X). The wet cake (1.24 kg) was dissolved in
ethyl acetate
(6X-7X), stirring for 1-2 hr at 20-30 C. The solution was concentrated to 3X-
4X, keeping the
inner temperature below 40 C. Isopropyl alcohol (9.5X-10.5X) was added, and
the solution was
concentrated to 4-5X, keeping an inner temperature below 40 C. Cool the
solution to -10-0 C,
filter the resulting solid, and rinse with cold isopropyl alcohol. Dry product
at 40-50 C for 16-20
hr. Yield = 1.09Kg. purity = 100%.
[0189] While certain embodiments of the present invention have been shown and
described
herein, it will be obvious to those skilled in the art that such embodiments
are provided by way of
example only. Numerous variations, changes, and substitutions will now occur
to those skilled in
the art without departing from the invention. It should be understood that
various alternatives to
the embodiments of the invention described herein may be employed in
practicing the invention.
It is intended that the following claims define the scope of the invention and
that methods and
structures within the scope of these claims and their equivalents be covered
thereby.
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